Table of contents :

• coprozoa : protozoa which are found in fecal matter outside the body, but which do not inhabit the intestine

 
• Acanthamoebidae
• Acanthamoeba : genus of free-living ameboid protozoa found usually in fresh water or moist soil
• Acanthamoeba astronyxis
• Acanthamoeba castellanii
• Acanthamoeba culbertsoni
• Acanthamoeba  hatchetti
• Acanthamoeba polyphaga
• Acanthamoeba  rhysodes
They form acanthopodia.
=> acanthamebiasis : opportunistic infections from stagnant water (cutaneous ulcers, conjunctivitis and Acanthamoeba keratitis (expecially in contact lenses carriers, the temperature and moist environment of the eye serve as a good medium for the growth and proliferation of the amebas and is not necessarily associated with immunosuppression but rather with trauma) ==olfactory nerve (?) or hematogenous spread==> primary amebic meningoencephalitis (PAM)
• acute, sometimes associated with spontaneous recovery
• subacute
• chronic granulomatous amebic encephalits (GAE) in chronically ill and debilitated individuals. Subclinical infections due to free-living amebas are probably common in healthy individuals with the protozoa living as "normal flora" in the nose and throat.
• Euglenozoa [Euglenida : an order of plantlike, flagellate protozoa (class Phytomastigophorea, subphylum Mastigophora) having green chromatophores when present; 1-2, rarely more, flagella protruding from an anterior invagination; and a small stigma located anteriorly in colored forms. The organisms are usually found in fresh water, although some inhabit salt or brackish water, and a few are parasitic]
• Kinetoplastida / Protomastigida / Protomonadina : an order of flagellate protozoa (class Zoomastigophorea, subphylum Mastigophora), many species of which are free living, although most are parasites of plants, invertebrates, and vertebrates. Kinetoplastids have 1-2flagella arising from a depression in the cell body and usually contain a conspicuous kinetoplast located near the flagellar basal bodies. The order comprises two suborders:
• Bodonina
• Trypanosomatidae (1 only flagellum) [Trypanosomatina : a suborder of parasitic protozoa (order Kinetoplastida, class Zoomastigophorea) comprising the hemoflagellates, which are found in the hosts' blood, lymph, and tissues, and are characterized by a leaflike or rounded body with one nucleus, one flagellum that is free or attached to the body by an undulating membrane, and a relatively small compact kinetoplast. All trypanosomatids have morphologically distinct stages in their life cycles during which the organisms of one genus may pass through forms characteristic of other genera of the suborder. These forms include: amastigote, choanomastigote, epimastigote, opisthomastigote, promastigote, and trypomastigote. Not all species pass through all of the stages, but all have at least 2 such forms during their development.

amastigote (in invertebrates) => metacyclic trypomastigote (in vector) => promastigote (the free flagellum and kinetoplast are anterior to the nucleus) => epimastigote (a short undulating membrane) => blood stream trypomastigote (the undulating membrane and kinetoplast are located posterior to the nucleus). Representative genera include :
• Blastocrithidia : a genus of protozoa parasitic in arthropods and other invertebrates, which pass through epimastigote, amastigote, and presumably promastigote developmental stages in their life cycle.
• Crithidia
• Leishmania : a genus of flagellate protozoa (suborder Trypanosomatina, order Kinetoplastida) comprising parasites of worldwide distribution, several species of which are pathogenic for humans. The organisms have 2 morphologic stages in their life cycle: amastigote (Leishman-Donovan body), found intracellularly in the vertebrate (i.e., human) host; and promastigote (leptomonad), found in the digestive tract of the invertebrate host (i.e., phlebotomine sandfly) and in cultures. Because all species are morphologically indistinguishable, the organisms have usually been assigned to species and subspecies according to their geographic origin, the clinical syndrome they produce, and their ecologic characteristics, or they have been separated on the basis of their tendency to cause visceral, cutaneous, or mucocutaneous leishmaniasis.
Epidemiology : collectively, the diseases are now routinely found in 88 countries across 5 continents, with an estimated 350 million people at risk. Around 1.5 million new cases of cutaneous leishmaniasis occur every year. Up to 90% of these occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia and Syria.
Transmission : they are transmitted into mammalian hosts in their promastigote form and are soon phagocyted by macrophages : they can replicate in phagolysosomes of RES cells throughout the body, especially in the liver, spleen, bone marrow, lymph nodes, and skin. Although lipophosphoglycan (LPG) is involved in the transient inhibition of phagolysosomal fusion soon after Leishmania enters the host cells, this inhibition is not essential for Leishmania survival within macrophages : rather it is important in resisting the effects of intracellular oxidants. Localization (cutaneous, mucocutanous or visceral) depends on strength (high, moderate or weak, respectively) and T_h polarization (T_h1 or T_h2, respectively) of immune response.
• Leishmania aethiopica species complex
• Leishmania aethiopica (a.k.a. Leishmania tropica aethiopica)
Transmission : reservoirs : Procavia capensis, Heterohyrax brucei ; vectors : Phlebotomus pedifer in Kenya and Phlebotomus longipes in Ethiopia
Epidemiology : highlands of Ethiopia and Kenya. The rate of leishmanin positivity in 10 villages in Upper Awash, northeastern Ethiopia ranged from 16 to 65 %, with the overall prevalence of 33%^ref; the figure was 5% in the Ethiopian Rift Valley province^ref. Leishmania is transmitted by sandflies; various animals -- especially rodents -- act as reservoirs
=> Old World cutaneous leishmaniosis / Aden ulcer : erythema on face (zygoma, temples, nose), hand palms and foot backs => macule => papule on bite point => nodule => indolent ulcer => heals, leaving an atrophic scar, or undergoes bacterial overinfection, nausea and vomiting, and lymphadenitis
• Ethiopian cutaneous leishmaniasis : lesions are less inflamed and more chronic than those of other Old World forms, and generally last for several years; the condition is usually self-limited but may develop into ...
• diffuse or anergic cutaneous leishmaniasis : local and hematogenous spread from a primary lesion to produce generalized nodular lesions resembling those of lepromatous leprosy in the skin and sometimes involving the nasal mucosa and laryngopharynx. Individuals with this form of the disease do not develop an effective immune response to the infection.
• leishmaniasis recidivans : a relapsing form of either wet or dry cutaneous leishmaniasis, resembling tuberculosis of the skin, in which the ulcer heals incompletely, scarring centrally but spreading peripherally, or heals and recrudesces at the edge of the ulcer; it may last for many years
• Leishmania donovani species complex : all multiply in the reticuloendothelial cells and spread to the lymph nodes and then hematogenously throughout the body. The subspecies can be distinguished only by differences in the epidemiology, clinical features, and response to treatment
• Leishmania donovani
Epidemiology : tropical and subtropical regions of the world. It has traditionally been divided into 3 different forms according to geographical distribution, vector, and other factors, but such a distinction may prove to be invalid. VL is largely found in the eastern part of India mainly in Bihar state and to some extent in its bordering states like West Bengal and Uttar Pradesh. The main vector in India is Phlebotomus argentipes. VL decreased in India during the 1950's after extensive spraying with DDT as part of the malaria control programme, but has been increasing again since the 1960's. A large epidemic occurred in Bihar state in the 1990's. VL is typical in rural areas and it is not known whether the 2 cases in this report have been residents in endemic areas primarily Bihar state or have been long-term residents in Mumbai^ref. Most of the approximately 500,000 cases of VL reported worldwide affect the rural poor in India, Nepal, Bangladesh, Sudan, and Brazil^ref. Georgia : only 1-5 cases of VL were recorded annually before 1995, but 174 cases of leishmaniasis were registered in  in 2006, including 103 cases in Tbilisi. According to the experts, the most dangerous territories for leishmaniasis are the central districts of Tbilisi: Vake, Vera and Mtatzminda.
=> visceral leishmaniosis (VL) / kala-azar / tropical splenomegaly / black, cachectic, cachexial, or Dumdum fever : after 4-10 months incubation =>
• gradual onset, prolonged, irregular fever with chills that often rises and falls twice/day
• nausea and vomiting
• diarrhea
• fatigue
• weight loss, emaciation, cachexia / phthisis
• anemia
• leukopenia
• hypergammaglobulinemia
• diffuse skin hyperpigmentation (earth-gray color) on forehead, abdomen, hands, and feet in light-skinned persons
• cutaneous nodule may or may not appear at the site of the bite
• dizziness
• cough
• pronounced splenomegaly (hard, non-tender)
• hepatomegaly (granulomatous hepatitis), jaundice and ascites
• generalized lymphadenitis
• skin lesions in dark-skinned persons
• signs of bleeding (petechiae, epistaxis, bleeding gums)
Onset may also be acute, with the above manifestations appearing a few weeks after infection
=> post–kala-azar dermal leishmaniasis (PKDL) / dermal leishmanoid, leishmanoid, and post–kala-azar dermal leishmanoid : a condition associated with visceral leishmaniasis, commonly characterized by the appearance of hypopigmented or erythematous macules on the face and sometimes on the extremities and trunk; the facial lesions gradually progress to papules or nodules that resemble those of lepromatous leprosy. It is seen in about 20% of Indian patients, usually occurring years after the treatment of or spontaneous recovery from visceral leishmaniasis, and it may last for as long as 20 years. When the condition affects patients in East Africa (2% and China (rare), it usually occurs shortly after or during treatment and usually does not persist
Death within 2 years due to infections.
• Leishmania donovani chagasi
Epidemiology : South America, Central America, and Mexico. Human and canine visceral leishmaniasis, VL, is well known but rare in Venezuela. The incidence of human VL was 0.2 cases per 100 000 population 1995 to 2000, or 242 cases. However, 26% of the cases originated from Isla Margarita. In the same period, up to 25% of dogs tested on the island were seropositive for Leishmania (PAHO)^ref.
Transmission : a zooanthroponosis : reservoirs are Canis familiaris (may become infected and even infectious without showing any signs of the disease), Vulpes spp., Felis catus; vector : Lutzomyia longipalpis, but also other species such as Lutzomyia intermedia may be vectors
=> South-American visceral leishmaniasis
• Leishmania donovani donovani (a.k.a. Leishmania donovani)
Epidemiology : older children or young adults in eastern India, Bangladesh, and Hyderabad, Sind province, Pakistan
Transmission : a zooanthroponosis transmitted by the sandfly Phlebotomus argentipes, a sandfly that commonly rests in houses and cattle sheds. Consequently spraying the interior surfaces of these structures with DDT, or other insecticides, should do much to kill the vectors. Incidentally this is one of the very few sandflies whose larval habitats are reasonably well known, namely moist soil with organic content in and close to houses. During the Malaria Control and Malaria Eradication campaigns in India in the 1960s, there was almost a cessation of visceral leishmaniasis transmission, because indoor residual spraying against the Anopheline mosquito vectors of malaria also resulted in killing endophilic sandfles. But with the deterioration of the malaria campaigns sandflies returned, and in 1977 there were some 100 000 cases of visceral leishmaniasis in Bihar state . There are no reservoir hosts of L. d. donovani in India, although in other countries such as Sudan and Ethiopia various rodents and Serval cats (Felis serval) and genets (Genetta genetta) can be reservoir hosts of L.d.donovani
=> Indian visceral leishmaniosis (VL) / classic visceral leishmaniosis
Treatmentoptions for visceral leishmaniasis are limited and have traditionally been unsatisfactory because of drug toxicities, poor responses, multiple disease syndromes, and other factors - including recently, the emergence of antimony-resistant strains. Sodium stibogluconate (10÷60 days course depending on where the disease was contracted and whether illness is first or second episode), a historically effective and affordable pentavalent antimonial compound, is associated with fatal toxic effects^{ref1, ref2, ref3}, and in some regions its use has led to the development of resistant strains of Leishmania donovani^ref, with the result that fewer than 50% of treated patients are cured^{ref1, ref2, ref3, ref4}. In regions where antimony resistance is prevalent, intravenous amphotericin B (desoxycholate) (Fungizone, Sarabhai Piramel Pharmaceuticals) is used, but it is expensive and may require weeks of hospitalization with intensive clinical and laboratory monitoring. Liposomal formulations of amphotericin B, which require a shorter treatment course (5 days) and have fewer side effects, remain unaffordable at nearly 30 times the cost of conventional formulations^{ref1, ref2}. Miltefosine, the first effective oral therapy for visceral leishmaniasis (20 days course (leishmaniasis major responds in 10 days))^ref, is expensive^ref, is potentially teratogenic, and has significant gastrointestinal side effects^ref. Safe, effective, and affordable treatments for visceral leishmaniasis in regions where the disease is endemic are urgently needed, particularly in formulations that are compatible with rural settings. Because humans are the reservoir for visceral leishmaniasis in the Indian subcontinent, the infection could be eliminated with widespread treatment of patients and rigorous vector control^ref (although elimination may not be possible in regions where zoonotic visceral leishmaniasis is prevalent, such as Brazil). Paromomycin, an aminoglycoside antibiotic, has been shown to have a dose–response efficacy in the treatment of visceral leishmaniasis when administered intramuscularly at a dose of 12, 16, or 20 mg of sulfate per kilogram of body weight daily for 21 days^{ref1, ref2}. A phase 3, multicenter, noninferiority clinical trial showed that paromomycin was noninferior to amphotericin B for the treatment of visceral leishmaniasis in India^ref
• Leishmania infantum species complex
• Leishmania infantum (a.k.a. Leishmania donovani infantum)
Epidemiology : children between ages 1 and 4 in Mediterranean region (in Italy expecially zymodeme MON-1 / LON-49), sub-Saharan and East Africa, the Middle East, and China. Human and canine leishmaniasis in asymptomatic and symptomatic population in Northwestern Greece^ref.
• China : visceral leishmaniasis or Kala Azar was highly prevalent in  but has been effectively controlled since 1958. Only sporadic cases occur in the hilly and newly reclaimed desert areas in northwestern China^ref. Genetic typing of recent cases from Xinjiang province has found that Kala Azar from eastern China is similar to that from India^ref. A review of leishmaniasis in China concluded that apart from sporadic cases in Xinjiang and western Inner Mongolia, leishmaniasis had been brought under control in China^ref. It should be noted that leishmaniasis is also found in neighboring Kazakhstan
Transmission : zooanthroponoses; reservoir : Canis familiaris, Vulpes spp., jackals, and Rodentia; vectors: Phlebotomus perniciosus and Phlebotomus major in the Mediterranean littoral, Phlebotomus ariasi Middle East (usual vectors Phlebtomus papatasi and Phlebotomus caucasicus), sub-Saharan and East Africa (usual vectors Phlebotomus orientalis and Phlebotomus martini), and China (reservoir : Canis familiaris; usual vectors Phlebotomus chinensis and Phlebotomus sergenti).
=> Mediterranean or infantile visceral leishmaniasis
=> Chinese leishmaniosis
=> viscerotropic cutaneous leishmaniasis : a rare type of infection found in northeastern Saudi Arabia; after infection, instead of the usual cutaneous symptoms, fever and other systemic symptoms are seen and Leishmania can be detected in internal organs.
=> wet cutaneous (exception in this complex !) leishmaniasis / rural cutaneous leishmaniasis / Oriental sore / Aleppo boil / tropical sore or ulcer / Delhi boil / Biskra stud (reservoirs : desert Rodentia such as ground squirrels and gerbils (particularly Rhombomys opimus and Meriones spp.); vector : Phlebtomus papatasi, Phlebotomus sergenti) : infection is acute, rapidly evolving, and characterized by multiple sores with inflammation, ulcer, and crusting.
=> leishmaniasis recidivans : a relapsing form of either wet or dry cutaneous leishmaniasis, resembling cutaneous tuberculosis, in which the ulcer heals incompletely, scarring centrally but spreading peripherally, or heals and recrudesces at the edge of the ulcer; it may last for many years
• Leishmania major species complex
• Leishmania major (a.k.a. Leishmania tropica major)
Epidemiology : first discovered in rodents in south-central Asian areas of the former USSR; central to southwest Asia extending into northern Afghanistan, Pakistan, and northwest India
Transmission : zooanthroponosis; reservoirs : Rhombomys opimus, Psammomys obesus, Arvicanthis niloticus. In Sind (Pakistan). Meriones spp. (gerbils), which are granivorous and nocturnal in their habits. In north-west India Meriones hurrianae and Meriones lybicus (> Meriones crassus and Tatara indica) are thought to be the main vertebrate hosts, and may prove to be the reservoir hosts in the Sind area of Pakistan; vectors : Phlebotomus caucasicus, Phlebtomus papatasi, Phlebotomus salehi, Phlebotomus mongolensis, Sergentomyia clydei
Pathogenesis : infection with Leishmania major induces a protective immune response and long-term resistance to reinfection, which is thought to depend upon persistent parasites. Although effector CD4⁺ T cells are lost in the absence of parasites, central memory CD4⁺ T (T_CM) cells are maintained. Upon secondary infection, these central memory T cells become tissue-homing effector T cells and mediate protection. Thus, immunity to L. major is mediated by at least 2 distinct populations of CD4⁺ T cells: short-lived pathogen-dependent effector cells and long-lived pathogen-independent central memory cells. These data suggest that central memory T cells should be the targets for nonlive vaccines against infectious diseases requiring cell-mediated immunity^ref.
=> Old World rural cutaneous leishmaniosis / Aden ulcer / Oriental sore wet variety in Eastern Europe and Northern Africa : macule => papule on bite point => nodule => indolent ulcer => heals, leaving an atrophic scar, or undergoes bacterial overinfection, nausea and vomiting, and lymphadenitis
• dry or urban zoonotic cutaneous leishmaniasis (ZCL) : a type found mainly in large urban areas in the Middle East, the Mediterranean region, and the Indian subcontinent, transmitted by the vectors Phlebotomus sergenti and Phlebotomus papatasi. The reservoir may be either human or Canis familiaris. A slowly developing single lesion that persists for a year or more is typical
• leishmaniasis recidivans : a relapsing form of either wet or dry cutaneous leishmaniasis, resembling cutaneous tuberculosis, in which the ulcer heals incompletely, scarring centrally but spreading peripherally, or heals and recrudesces at the edge of the scar; it may last for many years
• sometimes causing viscerotropic cutaneous leishmaniasis
Prevention : it is generally agreed that in most cases, compulsory treatment of those infected with Leishmania major (ZCL) is the best strategy to control outbreaks. However, if the vector proves to be Phlebotomus papatasi, then it may be appropriate to spray the internal surfaces of houses and outhouses with residual insecticides. In fact, spraying was believed to have greatly reduced leishmaniasis in India when used to kill the indoor-resting anopheline vectors of malaria. However, such an approach will not kill sandfly adults resting outside homes, such as in rodent borrows. Although it might be argued that aerial spraying is more appropriate, this approach has rarely (if ever) been successful in controlling sandfly populations; even when used against mosquito vectors of malaria and dengue, aerial spraying has often failed. Moreover, it requires considerable organization and high costs, which most would consider totally unjustified, especially as the actual sandfly vector and their habits (such as resting places) have not actually been identified. Furthermore, outdoor spraying does not usually remain effective for more than 2 to 3 months. I would be surprised if there were "continuous migration" of sandflies from Afghanistan into the Sindh or other areas of Pakistan, as suggested in the report. Although they have been known to fly up to 2.2 km over a few days and might be dispersed considerable distances with the wind, sandflies generally fly very short distances. Nevertheless, human population movements, such as migration of labour forces and/or changes in rodent populations are more likely to have aided the reported increases in leishmaniasis.
Leishmania tropica species complex
• Leishmania tropica (a.k.a. Leishmania nilotica, Leishmania tropica minor, and Leishmania tropica tropica)
Epidemiology : in eastern Mediterranean sea, including Iran, Iraq, India, and Israel (95 cases, 24 of them Tiberias residents (increased by 150% in 2003 compared to 2002. The most dramatic rise was in Tiberias, where the Health Ministry registered 44 cases in the past 5 years. Ha'emek Hospital in Afula reported 40 cases since September 2002 -- 10 times more than in the previous 3.5 years). It was once prevalent in the Arava, the Dead Sea area and the Jordan Valley), India, Pakistan, Afghanistan. Leishmaniasis is endemic in Iraq : high-risk areas for visceral Leishmaniasis are Greater Bagdad area, Missan, Thi-Qar, and Basrah governates. The Iraqi health authorities reported in 2001 10.9 cases per 100 000 population of visceral leishmaniasis, which extrapolated mean that about 25 cases can be expected in returning US troops. The above numbers suggest a significantly higher transmission rate than reported in 2001. An incidence of cutaneous leishmaniasis as high as 200 cases out of 750 men in a single unit has been reported : it is not impossible with soldiers staying outside in a highly endemic area at the height of the transmission season. So far, there have been 2 cases of visceral leishmaniasis reported. Around 4% of Afghans are infected by leishmaniasis, and Kabul is home to 33% of these cases (67,500 people) : in Muslim countries, such as Afghanistan, affected women are often forbidden to breast-feed or have sex. Afghanistan's once-effective control programme has been destroyed by 20 years of conflict.
Transmission : an anthroponosis with vector : Phlebtomus papatasiin southern France, Italy, and certain Mediterranean islands, Phlebotomus sergenti in Iran, Iraq, and India (a domestic species that lives and breeds in and around houses and therefore has often been controlled by spraying the inside surfaces of houses with residual insecticides), Phlebotomus arabicus (the Galilee region of northern Israel^ref; Procavia capensis as probable reservoir hosts : the disease may break out in areas where new neighborhoods are being built. Large rocks are moved, and such circumstances bring the hyraxes close to human beings). Because Canis familiaris can become infected and develop canine leishmaniasis, they are sometimes referred to as alternative hosts, but not reservoir hosts. Since the sand fly is a low-flying insect, many leishmaniasis victims are children, who get bitten in the face; adults usually are affected in their lower exposed limbs, particularly their legs. Human to human transmission may also occur.
=> Old World cutaneous leishmaniosis / Aden ulcer / Oriental sore dry variety / Aleppo button / Biskra stud / the Lily of Jericho : incubation period of 6 months => macule => papule on bite point => nodule => indolent ulcer => heals, leaving an atrophic scar, or undergoes bacterial overinfection, nausea and vomiting, and lymphadenitis. By taking away the crust many protuberances appear (Montpellier sign or nail sign)
Prognosis : self-limiting within 6-12 months.
Prevention : in Middle-East immunization is obtained by injecting promastigotes in skin of covered body regions in order to prevent infection on exposed regions. Bed nets should be offered to those most at risk: the families and neighbours of infected people.
• Leishmania mexicana species complex
• Leishmania mexicana
• Leishmania mexicana amazonensis
Epidemiology : Amazon region of Brazil and neighboring countries (extreme northeast of Paraguay) and in Trinidad
Transmission : reservoirs : Oryzomys capito, Oryzomys concolor, Oryzomys macconnelli, Proechimys guyanensis, Heteromys anomalus, Neacomys spinosus, Nectomys squamipes, Dasyprocta spp., Marmosa murina, Marmosa mitis, Marmosa fuscata, Caluromys philander, Metachirus nudicaudatus; vector : Lutzomyia flaviscutellata.
A single lesion is usually present but a few cases of diffuse cutaneous leishmaniasis have been reported.
• Leishmania mexicana mexicana
Epidemiology : south-central Texas
Transmission : reservoirs : Ototylomys phyllotis, Heteromys desmarestianus, Nyctomys sumichrasti, Sigmodon hispidus; vector : Lutzomyia olmeca, Lutzomyia diabolica. The transmission
cycle involves rodents, especially Neotoma micropus, and the vector in this instance is possibly Lutzomyiaanthophora. In southern Texas, seropositive coyotes have been found, and there has been a report of an infected domestic cat. As leishmaniasis is common from Mexico down through much of South America, it is not surprising that it is occasionally reported in Texas. In contrast, the chances of transmission of leishmaniasis from people (or pets) infected in Iraq, Afghanistan, or the Middle East entering  the USA are minimal, although obviously health authorities should be aware of the possibility of transmission and  human cases so that rapid diagnosis and treatment can be made.
=> chicle, chiclero or chicheros ulcer : an endemic, zoonotic form of New World cutaneous leishmaniasis, found mainly in forest workers in the Yucatan and adjacent areas of Mexico, Belize, and Guatemala. It is characterized by one or a few lesions that are usually self-limited and heal within 6 months, except when the pinna of the ear is involved, in which case over a period of many years the chronic lesion invades and slowly destroys the cartilage of the ear.
• Leishmania mexicana venezuelensis
Transmission : in Leishmania mexicana-infected Lutzomyia longipalpis sand flies the anterior midgut is blocked by a gel of parasite origin, the promastigote secretory gel, including the filamentous proteophosphoglycan (fPPG)^ref
• Leishmania pifanoi (a.k.a. Leishmania mexicana pifanoi) in Venezuela and certain areas of Brazil
Proteomics : lipophosphoglycan (LPG) binds to CD209 / DC-SIGN
Transmission : vector : Lutzomyia longipalpis (in Venezuela parasite rates in caught vectors range from 0.15% (Isla Margarita) to 3% (Aragua State))
=> New World cutaneous leishmaniosis / American cutaneous leishmaniasis : their lesions develop and heal similarly to those of the Old World forms but tend to be less nodular and more ulcerative and destructive
=> diffuse or anergic cutaneous leishmaniasis : local and hematogenous spread from a primary lesion to produce generalized nodular lesions resembling those of lepromatous leprosy in the skin and sometimes involving the nasal mucosa and laryngopharynx. Individuals with this form of the disease do not develop an effective immune response to the infection.
=> leishmaniasis recidivans : a relapsing form of either wet or dry cutaneous leishmaniasis, resembling tuberculosis of the skin, in which the ulcer heals incompletely, scarring centrally but spreading peripherally, or heals and recrudesces at the edge of the scar; it may last for many years
• Viannia
• Leishmania braziliensis species complex (a.k.a. Leishmania viannia, Leishmania brasiliensis) : a taxonomic complex comprising the subspecies that cause mucocutaneous leishmaniasis in its various forms; all of the subspecies develop in the midgut, foregut, and hindgut of their sandfly vectors
• Leishmania braziliensis (a.k.a. Leishmania viannia brasiliensis)
Epidemiology : Brazil, Peru, Ecuador, Bolivia, Venezuela, Paraguay, and Columbia
Transmission : reservoirs : domestic animals (Oryzomys concolor, Oryzomys nigripes, Oryzomys capito, Proechimys guyanensis, Canis familiaris, Rattus norvegicus); vectors : Psychodopygus amazonensis, Psychodopygus paranensis, Psychodopygus wellcomei, Lutzomyia anduzei, Lutzomyia intermedia, Lutzomyia longipalpis (Paraguay^ref). Lutzomyia miganei, Lutzomyia pessoai, Lutzomyia shannoni, Lutzomyia whitmani
=> New World cutaneous leishmaniosis : macule => papule on bite point => nodule => indolent ulcer => heals, leaving an atrophic scar, or undergoes bacterial overinfection, nausea and vomiting, and lymphadenitis
• diffuse or anergic cutaneous leishmaniasis : local and hematogenous spread from a primary lesion to produce generalized nodular lesions resembling those of lepromatous leprosy in the skin and sometimes involving the nasal mucosa and laryngopharynx. Individuals with this form of the disease do not develop an effective immune response to the infection. It spreads to the nasal or oral mucosa, with naso-oropharyngeal symptoms sometimes appearing several years after resolution of the primary lesion(s) and sometimes while the primary lesions are present. Manifestations include chronic nasal symptoms, especially of the anterior nasal septum, progressing to erythema => papule on nose ("tapir nose")=> naso-oropharyngeal destruction. Secondary bacterial (or fungal) infections and associated problems are common
• mucocutaneous leishmaniasis / espundia : chronic, progressive metastatic spread of the lesions to the nasal, pharyngeal, and buccal mucosa months to years after the appearance of the initial cutaneous lesion, which has usually healed. It is often associated with mutilating destruction of the nasal septum, palate, lips, pharynx, and larynx
Leishmania peruviana (a.k.a. Leishmania viannia peruviana)
Epidemiology : in the Peruvian Andes only at altitudes of 900 to 3000 meters
Transmission : reservoir : Canis familiaris; vectors : Lutzomyia verrucarum, Lutzomyia peruensis)
=> New World cutaneous leishmaniosis / American cutaneous leishmaniasis / uta : their lesions develop and heal similarly to those of the Old World forms but tend to be less nodular and more ulcerative and destructive
• Leishmania guyanensis species complex
Leishmania guyanensis (a.k.a. Leishmania viannia guyanensis)
Transmission : reservoirs : Choloepus spp., Tamandua tetradactyla, Didelphys marsupialis; vector : Lutzamyia umbratilis
=> New World cutaneous leishmaniosis / American cutaneous leishmaniasis / pian bois / forest yaws : their lesions develop and heal similarly to those of the Old World forms but tend to be less nodular and more ulcerative and destructive
• Leishmania panamensis (a.k.a. Leishmania viannia panamensis)
Epidemiology : Panama and adjacent areas of Central America and Colombia.
Transmission : reservoirs : Choloepus hoffmanni, Bradypus infuscatus; vector : Lutzomyia trapidoi
=> New World cutaneous leishmaniosis : spread to the nasal or oral mucosa, with naso-oropharyngeal symptoms sometimes appearing several years after resolution of the primary lesion(s) and sometimes while the primary lesions are present. Manifestations include chronic nasal symptoms, especially of the anterior nasal septum, progressing to erythema => papula on nose ("tapir nose")=> naso-oropharyngeal destruction. Secondary bacterial (or fungal) infections and associated problems are common.
• mucocutaneous leishmaniasis / espundia : chronic, progressive metastatic spread of the lesions to the nasal, pharyngeal, and buccal mucosa months to years after the appearance of the initial cutaneous lesion, which has usually healed. It is often associated with mutilating destruction of the nasal septum, palate, lips, pharynx, and larynx
• Leishmania garnhami (a.k.a. Leishmania (Viannia) garnhami) : a species similar to L. mexicana amazonensis isolated from cases of cutaneous leishmaniasis in the region of the Venezuelan Andes
Mucocutanous leishmaniosis occurs in individuals with TNF-a-308 polymorphism.
• unclassified Leishmania
• Leishmania archibaldi
Transmission : vectors : Phlebotomus orientalis, Phlebotomus martini, Phlebotomus celiae
=> visceral leishmaniosis / black fever / Dumdum fever
East-African or Sudan leishmaniosis
Epidemiology : leishmaniasis is known to occur in outbreaks facilitated by famine and HIV co-infection. The last major outbreak of leishmaniasis in the southern Sudan was from 1984 to 1994, when the WHO estimated that 100 000 people died out of a population of 300 000 in the Western Upper Nile State. The highest prevalence of leishmaniasis in Paraguay is found in the southeastern part, and both cutaneous and mucocutaneous forms are seen : > 90% of cases come from the 3 departments of Caaguzu, Canendiya and San Pedro with reported incidence of about 50 per 100 000 population per year. > 250 cases of cutaneous leishmaniasis have been reported from January to May 2004. Between 30 and 40% of dogs tested positive in a recent survey. Visceral leishmaniasis is very rare, which makes these cases unusual.
Pathogenesis : negative leishmanin skin test, CD3 and CD4 lymphocytopenia, and significantly reduced numbers of memory CD4⁺ T cells were found in visceral leishmaniasis (VL) patients compared to treated VL patients or persons with self-limiting asymptomatic infection. The proportion of CD4⁺ and CD8⁺ T cells that produced IFN-g and IL-4 after stimulation with PMA and ionomycin was significantly reduced in VL patients compared to sub-clinical and asymptomatic infections or healthy controls. Plasma concentrations of IFN-g and IL-10 were elevated in VL^ref
Laboratory examinations :
• normocytic anemia, leukopenia, thrombocytopenia
• May-Grunwald and Giemsa staining
• culturing in Novy-Mac Neal-Nicolle (NNN) medium
• leishmanin Montenegro intradermoreaction or Napler formol-gellification test (due to high [Ab])
Therapy : intramuscular antimony (Sb-GlcNMe) or intravenous amphotericin B. The primary unmet need is for oral therapy. Of the several drugs in clinical development, miltefosine is unique in being an oral agent with efficacy against both visceral and cutaneous disease. Sitamaquine is an oral agent with substantial but not sufficient efficacy against visceral disease. Oral fluconazole has been shown to be more effective than placebo in one instance: for Leishmania major cutaneous disease from Saudi Arabia. Paromomycin is in widespread trial. Topical paromomycin formulations are being tested for cutaneous disease, and intramuscular paromomycin is in Phase III trial for Indian visceral disease. The most likely replacements for present therapy are oral miltefosine for many of the visceral and cutaneous syndromes, intramuscular paromomycin for visceral disease and topical paromomycin for some forms of cutaneous disease^ref. Over 30 days of intense feeding (?)
Prevention : there is no vaccine
Web resources : Leishmania genome network
• Leptomonas
• Trypanosoma (10-1200 mm) : a genus of protozoa comprising hemoflagellates parasitic in invertebrates and vertebrates, including humans; several species are pathogenic. Their life cycle involves amastigote, promastigote, epimastigote, and trypomastigote stages; the first 3 stages are found in the vector (usually a bloodsucking invertebrate) and the last in the vertebrate (definitive) host.
• in some systems of classification, trypanosomes are categorized in 2 groups according to where they develop in the digestive system of the vector:
• salivaria, including the subgenera Duttonella, Nannomonas, and Trypanozoon
• stercoraria, including the subgenera Megatrypanum, Herpetosoma, and Schizotrypanum
• another system classifies them into 4 groups based on biological similarities:
• (1) lewisi group, including T. lewisi, T. duttoni, T. theileri, T. cruzi, T. nabiasi, T. melophagium, and T. rangeli;
• (2) vivax group, including T. vivax and T. uniforme;
• (3) congolense group, including T. congolense, T. dimorphon, and T. simiae;
• (4) brucei group, including T. brucei, T. gambiense, T. rhodesiense, T. evansi, T. equinum, and T. equiperdum
• Trypanosoma melophagium : a nonpathogenic stercorarian species commonly found in sheep worldwide and transmitted by the sheep ked, Melophagus ovinus.
• Trypanosoma neotomae : a species found in wood rats in California, possibly identical with T. cruzi.
• Trypanosoma rangeli : a nonpathogenic, stercorarian species infecting humans and various animals, especially cats and dogs, primarily in Venezuela, Brazil, Colombia, Costa Rica, El Salvador, Guatemala, and Panama, and usually transmitted by reduviid flies of the genus Rhodnius.
• Trypanosoma rotatorium : the type species of the genus, and found in the blood of several species of frogs.
• Trypanosoma simiae : a salivarian species found especially in East Africa and eastern Zaire, first reported from the monkey although its natural reservoir is the warthog, and usually transmitted by tsetse flies (Glossina spp.) but sometimes also by bloodsucking flies. It causes nagana in various domestic animals, being highly pathogenic for camels (causing death in several days), mildly pathogenic for goats, and apparently nonpathogenic for cattle, horses, and dogs.
• Trypanosoma suis : a species that causes nagana in pigs.
• Trypanosoma theileri : a large stercorarian species found in the blood of cattle worldwide, transmitted by tabanid flies, and usually nonpathogenic although under stressful conditions it may be associated with illness and perhaps death.
• Trypanosoma theodori : a nonpathogenic, stercorarian species similar to (and perhaps the same as) T. melophagium that is found in goats and has the hippoboscid Lipoptena caprina as an intermediate host.
• Trypanosoma uniforme : a tsetse fly–transmitted salivarian species similar to but smaller than T. vivax that is a cause of nagana in cattle, goats, sheep, and antelopes in Zaire.
• Duttonella
• Trypanosoma vivax : a tsetse fly–transmitted salivarian species found in many animals, including cattle, sheep, goats, camels, horses, antelopes, and giraffes in Africa, Central and South America, the West Indies, and Mauritius. It is a cause of nagana, the severity of which depends on the species affected, being fatal in certain types of cattle in certain areas.
• Nannomonas
• Trypanosoma congolense (a.k.a. Trypanosoma nanum) a tsetse fly–transmitted salivarian species found in Central Africa that is a cause of nagana in domestic animals, which is especially severe in cattle
• Trypanosoma dimorphon a tsetse fly–transmitted salivarian species widely distributed in Central Africa, which was formerly thought to be identical with T. congolense but has been shown to be a distinct species. It is found in horses, pigs, goats, sheep, cattle, and dogs, in the latter three of which it has been shown to be more pathogenic than T. congolense.
• Herpetosoma (Stercoraria section => replication in lower tract of vector digestive apparatus => transmission via vector stools)
• Trypanosoma lewisi (a.k.a. Trypanosoma (Herpetosoma) lewisi) a stercorarian species commonly found in the blood of rats worldwide, usually nonpathogenic in adults but causing lethal infection in sucklings, and transmitted by the rat flea, Nosopsyllus fasciatus. The species is much used in laboratory research.
• Trypanosoma rangeli
=> non pathogenic ? (reservoir : Canis familiaris, Felis catus, Cebus spp., Tamandua spp.; vectors : Rhodnius prolixus, Triatoma dimidiata : they can transmit it even through saliva)
• Schizotrypanum (Stercoraria section => replication in lower tract of vector digestive apparatus => transmission via vector stools)
• Trypanosoma cruzi (a.k.a. Trypanosoma triatomae and Schizotrypanum cruzi)^ref
• Trypanosoma cruzi cruzi
• Trypanosoma cruzi marinkellei
Only zymodemes Z1, Z2 and Z3 are pathogenic for Homo. Also schizodemes (genovars detected by DNA fingerprinting using EcoRI on ktDNA) exist. Obliged intracellular parasite.
Epidemiology : 18 countries on the American continent in 2 different ecological zones:
• the Southern Cone region, where the main vector lives inside human homes and in peridomiciliary areas
• Central America and Mexico where the main vector species lives both inside dwellings and in uninhabited areas
• Peru : a total population of 600 000 is estimated to live in areas of Chagas disease transmission. In 1999, the screening of donated blood yielded a rate of 0.8% positive results^ref. Endemic in 3 regions: southwest, including Arequipa, Moquegua, Tacna, and Ica Departments, sharing characteristics with Northern Chile and Bolivia, since Triatoma infestans is the only recognized vector; the Northeastern area, including coastal regions from La Libertad, Lambayeque, Piura, and Tumbes Departments, where house-based vectors such as Rhodnius ecuadoriensis have been identified; and the third area corresponds to the Northeastern region, including Amazonas, Cajamarca, and San Martin Departments, all of them in the basins of rivers tributary of Amazonas river, where the most important vector is Panstrongylus herreri, which also colonizes households.
Country-wide cross-sectional surveys in the 1980s found an overall prevalence of 17 million cases, with 4.8-5.4 million people exhibiting clinical symptoms, an annual incidence of 700,000-800,000 new cases and 45,000 deaths every year due to the cardiac form of the disease At present, estimates indicate an infection prevalence of 13 million, with 3.0-3.3 million symptomatic cases and an annual incidence of 200,000 cases in 15 countries; population exposed at risk : 90 millions. The suspicion that a patient in India may present a patent infection of some form of trypanosomiasis is not entirely improbable. On the contrary, suspected human cases of Trypanosoma lewisi, another murine parasite, have been reported in India (2 cases, 1974) and Malaysia (1 case, 1933). There have been other incidental reports as well. However, unlike T. cruzi, T. lewisi is transmitted by Xenopsylla cheopis and Nosopsylla fasciatus. The morphology of T. lewisi can be easily distinguished from T. cruzi. Moreover, assuming no travel-related exposure or blood transfusions in the recent case, it appears nearly impossible that T. cruzi, and most certainly the 2 African trypanosomes, would be endemic in India. Trypanosome parasites are found in a great variety of mammals, but less well known trypanosomes are found in fish (vectors being leeches), amphibians (vectors are mainly leeches), reptiles (vectors are phlebotomine sandflies, tsetse flies and leeches), and finally, avian trypanosomes transmitted by mosquitoes, simuliid black-flies, hippoboscid flies and the chicken mite (Dermanyssus gallinae)
Genomics : gene exchange between clones of different genotypes occurs via multiple and unusual mechanisms
Proteomics :
• Trypanosoma decay accelerating factor (T-DAF) prevents C-mediated lysis until it is neutralized by host Abs
• Tc52 protein binds to TLR2
• trans-sialidase (both membrane-bound and shed) has anti-AICD and costimulatory effects on CD4⁺ T cells, both depending on CD43
• pore-forming protein showing immunological crossreactivity to complement C9
Transmission :
• a percutaneous zooanthroponoses; reservoir : over 150 species from 24 families of domestic and wild mammals, including Canis familiaris, Felis catus, Rattus norvegicus, Mus musculus, Didelphis spp., Dasypus spp., Tamandua spp., Desmodes spp., Glossophaga spp., Carollia spp., Aotus spp., Saimiri spp., Ateles spp. (in the vertebrate host, it infects many different cells, but in the human host, the disease is conspicuously limited to the myocardium and to gut nerve fibres); vectors : Rhodnius prolixus, Triatoma infestans, Triatoma dimidiata, Triatoma sordida, Triatoma brasiliensis, Panstrongylus megistus, Rhodnius pallescens, Dipetalogaster maximum^ref
• transplacental transmission
• blood transfusion : only 5 cases of blood transfusion infections have been confirmed in the US (3) and Canada (2 : both immunocompromised by chemotherapy for cancer). The risk of infections through blood transfusions has been estimated to be between 1 per 43 to 1 per 1072 transfusions in different countries. However, the risk of being infected if receiving blood from a T.cruzi seropositive donor is most probably overestimated. Recent seroprevalence studies showed that approximately 0.1% of blood donors likely to have been born in or have traveled to disease-endemic countries were seropositive for T. cruzi. Moreover, American Red Cross studies of recipients of T. cruzi­seropositive blood and blood products showed no evidence of transmission. Travellers are rarely exposed to infection, and T.cruzi infection in travellers is exceedingly rare. The triatomid bug lives in cracks and crevices in mud walls, and it is therefore immigrants living under poor conditions for a prolonged time who may carry the infection and pass it on through blood transfusion. A study conducted in the same geographic area of the U.S. documents ratios of Chagas- seropositive blood donors ranging from one positive in 9,900 in 1996, to one in 7,200 in 1997, to one in 5,400 in 1998^ref.A new study, completed in November 2006, documents the ratio of Chagas-seropositive blood donors at approximately one in 2,000 (Dr. Susan L. Stramer, Executive Scientific Officer, American Red Cross; presentation at 2006 American Association of Blood Banks (AABB) "Ongoing Clinical Evaluations of a Chagas' ELISA in US Blood Donors; Trypanosoma cruzi Antibody Prevalence in Three Regions of the American Red Cross" 23 October 2006)
• solid organ transplantation : although routine serologic testing of organ and blood donors is performed in areas of Latin America where Chagas disease is endemic, no T. cruzi screening test is licensed in the USA. However, seroprevalence studies using research tests have documented the presence of T. cruzi antibodies in U.S. blood^ref and organ donor populations^ref. 2 cases of acute Chagas disease in heart transplant recipients were reported by 2 Los Angeles County hospitals in February 2006^ref. In the USA, one previous report documented T. cruzi transmission through solid organ transplantation, in which 3 organ recipients were infected^ref. Persons born outside endemic areas by infected mothers can be infected in utero with congenital Trypanosoma cruzi and may remain infectious
• oral transmission can cause microepidemics of acute Chagas disease^ref. No doubt oral transmission to humans has been occurring for a long time. However, in the context of high levels of vector transmission, these cases went unnoticed. In the 1990s human cases acquired by the oral route were reported.
• Shikanai-Yasuda et al. reported 3 cases by oral transmission, apart from one possibly by breast-feeding^ref.
• A year later, the same group reported an outbreak in 1986, with 26 patients that acquired Chagas´ disease with acute phase symptoms after a family gathering in the Northeastern state of Paraiba^ref.
• Brazil : since the decline of vector-transmitted disease in Brazil, 1st in the State of Sao Paulo in the 1970s and then in other states in the 1990s, oral transmission has been a subject of growing concern
• Santa Catarina : this Southern state has never been an endemic area for Chagas´disease. Although Panstrongylus megistus can be found in forest areas, they have not moved into homes, as in Bahia or Minas Gerais, states well North of Santa Catarina. Chagas´ disease in wildlife is common in Santa Catarina, as well as in coastal areas in South and Southeastern Brazil. A rather recent paper^ref reported that oral sporadic transmission seems to be rather common in certain rural areas. This has been reported also from the Amazon, associated with acai, a rain-forest fruit that is rather a fad in urban areas, causing a small boom in the acai industry. This fruit is processed much in the same way as sugar-cane, in order to obtain a paste. As the fruit is found in palm-like trees, a favorite habitat of triatomid bugs, the result is a fruit paste contaminated with Trypanosoma cruzi. The most probable explanation for the outbreak in Santa Catarina is that sugar-cane was harvested and kept in some kind of makeshift shed that harbored triatomid bugs, and the droppings of these bugs contaminated the sugarcane, resulting in a juice with T.cruzi. As sugarcane juice (locally called "garapa") is drunk fresh, immediately after processing, the risk of infection is high. Oral transmission of T.cruzi to mammals was first demonstrated experimentally in 1958 (Phillips NR, Thesis, University of London, cited by Hoare CA in "The Trypanosomes of mammals, Blackwell Scientific Publ., London 1972), when 50% of mice became infected after being fed T.cruzi-infected triatomid bugs. Ingestion of infected vectors was also found to be the main mode of transmission among wood-rats in north America (Ryckman & Olsen, J Med Entomol 1972,2:99). Triatomid bugs have a preference for feeding from the face of sleeping humans and shed the parasites in their feces after the blood meal. The parasites are then thought to infect humans through the mucus membranes in the mouth or the conjunctiva. There is no information on how long the epimastigotes of T.cruzi remain infective after being passed in bug feces, which seems to be a key parameter for food-borne transmission. Sugar cane juice, also known as "garapa," is a very common beverage all over the country and is made by crushing the cane. The triatomid insect vector may have been crushed during this process, or the cane could have become contaminated with infected bugs' feces. So far there have been 31 confirmed cases and  5 deaths; additional 64 suspected cases under investigation. There may have been > 50 000 possible exposures (which includes international travellers). All cases were apparently related to drinking garapa in cities along the northern beaches of the State (to name all the suspicious cities:  Itapoa, Garuva,  Joinville, Araquari, Sao Francisco do Sul, Balneario Barra do Sul, Barra Velha, Picarras, Penha, Navegantes, Itajai, Balnearion Camboriu, Camboriu, and Itapema) : 91% of the cases had ingested sugar cane juice at the Kiosk Barracao da Penha 2, between the municipalities of Navegantes and Pen-ha, on the side of the BR-101 highway by Kilometer 111. The test, conducted by the Department of Microbiology and Parasitology of the Federal University of Santa Catarina, proved the presence of the protozoan in a triatomid bug hidden in a towel -- a product that is also sold in this kiosk. Norms aimed specifically for the sale of sugar cane juice will take effect on 31 Mar 2005. ANVISA (the National Sanitary Surveillance Unit) announced that all persons who drank sugar cane juice from the kiosks along highway BR-101, between Picarras and Italjai, during the period 1 Feb 2005 through 23 Mar 2005 are to be considered inappropriate for blood donation.  There are 2 research papers referring to previous outbreaks of Chagas disease associated with the oral route of transmission (1968 in Teutonia RS^ref and 1991 - Catole do Rocha PB^ref), the larger of which presents 26 confirmed cases. Incubation period seems to be around 7-28 days, and the main signs and symptoms include high fever for > 5 days; myalgia; headache; orbital swelling and hepatosplenomegaly. In such cases diagnosis must be confirmed with serology (remember that many labs perform only IgG); IgM and direct visualization on smears. Treatment with either benzonidazol or nifurtimox must be provided ASAP for all acute cases, especially symptomatic ones. Cure rates are around 70%. For diagnosis in asymptomatic cases, we are recommending just serology IgG and IgM. In negative cases with > 30 days elapsed from exposure, close the case; < 30 days, repeat serology within 2-4 weeks. All positive cases must be confirmed with a 2nd serological exam or direct visualization of T. cruzi. The main factor for the risk of spreading Chagas disease by food and drink is the survival of the trypanosomes after they have left the intestine of the triatomid bug. How sensitive are they to changes in temperature, pH, and osmolarity? This will determine how long they can stay infective in bug feces on sugar cane. In 1968, a member of a farming community in Teotonia (Rio Grande do Sul) fell ill with a severe febrile illness. No one suspected Chagas disease, as there were no Reduviid bug vectors in the local dwellings. After much investigation, food borne transmission through vegetables served in the common dining-room was accepted as the cause. Possibly, marsupials had contaminated the vegetables by droppings from their anal glands, usually rich in T.cruzi. In 1986, another outbreak occurred, this time in Catole do Rocha (Paraiba). A large wedding anniversary party had been held on a farm. Days later, some of the guests fell ill with a febrile illness, similar to the one in Teotonia. Sugarcane juice and other foodstuffs or beverages had been contaminated by animal droppings. The couple that had celebrated their 50th anniversary eventually died as a consequence of Chagas disease acquired at the party. Recently, oral transmission of T.cruzi has been responsible for small outbreaks in the state of Para. Entire families acquired Chagas disease in the absence of insect vectors in their homes. These insects live in palm trees and, attracted by the lights, fall into the machinery used to grind acai to obtain juice (much the way sugarcane juice is obtained). The insects are ground and contaminate the juice with T.cruzi, transmitting the infection to those drinking it. All of these cases in Rio Grande do Sul, Paraiba and Para attracted the attention of scientists. The question which was brought forward was why didn't gastric juice destroy T.cruzi ? The physician Sonia Gomes Andrade from CPqGM, who specializes in experimental pathology, formulated an experiment: she introduced T.cruzi through a tube directly into the stomach of mice,. She studied the strains isolated from cases in Paraiba and Para. She observed that the parasite not only survived gastric juice but was able to infect the mice. They developed disease identical to the one produced when mice are infected directly via the bloodstream. The findings of the researcher confirm that T.cruzi, when swallowed, can cause infection through the digestive system. In the most common manner of infection, scratching, T.cruzi is able to penetrate the skin. It is easy to imagine that, when someone ingests a large quantity of parasites, the infection will be more severe. There is no reason to stop eating vegetables or drinking sugarcane or acai juice. The problem lies not with the kind of food but with T.cruzi. These are mainly parasites of biodem type III -- from wildlife -- that are able to cause infection through the digestive system. A biodem is a group of genetically close T.cruzi strains with similar characteristics. Biodem type III strains are, as a rule, highly pathogenic. In the experiment, a strain of this type showed a higher capacity to cross the gastric barrier and cause infection in mice than strains from biodems I and II.  It is significant to point out that biodem III strains are associated with wildlife disease cycles, causing outbreaks in places where Reduviid bugs are not domiciled. It seems beyond doubt that T.cruzi can infect hosts, including humans, by the oral route, but it still remains unclear how important this route of transmission is for maintaining infections in humans and causing outbreaks like the present one. The mouse experiment cited above confirms previous reports Hoft et al. Infect Immun 1996,64:3800-10] that T.cruzi can indeed infect the host through the gastric mucosa. The key question is how long a time T.cruzi can survive in feces outside the triatomid bug, and how long a time in different forms of fluids after the triatomid bugs have been crushed. Oral transmission, either from bug feces or from crushed bugs, presumes that T.cruzi can survive for at least several hours, possibly days, in juice. Information on this survival time is key to determining whether the present outbreak is a rare coincidence or just part of a more widespread problem.
• In Santarem township, in western Para state, 780 km from Belem (near the mouth of the Amazon river), 20 cases of Chagas' disease were confirmed by the Division of Health Surveillance (DVS) of the municipal health secretariat in July 2006 :  DVS believes the appearance of the new cases is due to drinking bacaba wine, made from the fruit of a palm (Oenocarpus bacaba) similar to that of the acai palm. The hemipteran vector was found in bunches of the berry-like fruit and could have been ground up with the fruit^ref.
During the past decades, after urban migrations, Chagas disease became frequent in cities and a health problem in non-endemic countries, where it can be transmitted vertically and by blood transfusion or organ transplantation.
Pathogenesis : parasite-derived danger signal (parasitokines, ...) => breakdown of self-tolerance => autoimmunity. It induces up-regulation of both Fas and FasL on parasite-specific IgG⁺ B cells and renders them susceptible to B cell-B cell killing (fratricide). Integration of T.cruzi kinetoplast DNA (kDNA) into the genomes of infected patients, as well as chicken and rabbit animal models, suggesting that horizontal gene transfer may play a role in T.cruzi host–parasite interactions. In the human chromosomes, 5 loci were identified as integration sites, and the beta-globin locus and LINE-1 retrotransposons were frequently targeted. Short repeated sequences in the parasite and the target host DNAs favor kDNA integration by homologous recombination. Introduced kDNA was present in offspring of chronically infected rabbits and in chickens hatched from T. cruzi-inoculated eggs. kDNA incorporated into the chicken germline was inherited through the F₂ generation in the absence of persistent infection. If this process involves the germline, integrated kDNA could theoretically alter human genetics through disruption of protein-coding sequences and promotion of recombination events between kDNA integration sites. kDNA integration represents a potential cause for the autoimmune response that develops in a percentage of chronic Chagas patients, which can now be approached experimentally^ref
=> Chagas' disease / American trypanosomiasis :
• 90% asymptomatic
• 10% symptomatic :
• acute phase : after 8-14 days incubation remitting or continuous fever appears. Infection through skin causes erythema nodosum (sometimes evolving to ulcer : chagoma) while infection through conjunctiva causes unilateral ophthalmia with palpebral edema, conjunctivitis and preauricular lymphadenitis(Romaña sign), replication in ...
• smooth muscle cells
• skeletal muscle cells
• cardiomyocytes => acute myocarditis
• CNS neurons => meningoencephalitis (10 %) and Castellani-Low symptom : a fine tremor of the tongue seen in sleeping sickness
Self-limiting or lethal within a month due mainly to heart failure. If pregnants are infected within month 3 => abortion. Congenital infection : splenomegaly.
• latency (from months up to 20 years)
• chronic phase (33%) : Chagas disease has a cronic course in various regions of the body. Replication in
• vegetative nervous system neurons causes functional incompetence and dilatations known as mega formations :
• chronic chagasic cardiomyopathy (CCC) (myocarditis => 25 % undergo cardiomegaly => congestive heart failure(1^st cause of heart failure in Latin America, 10% total mortality) => oedemas => sudden death)
• urinary apparatus
• megapelvis
• megaloureter
• megabladder
• bronchiectasis
• megabronchus
• digestive apparatus
• megapharynx (?)
• achalasia of the LES => megaesophagus and dysphagia
• achalasia of the pylorus / hypertrophic pyloric stenosis => megastomach / gastromegaly
• megaduodenum
• mega-gallbladder
• mega-common bile duct
• megaintestine (mega-small bowel)
• dilated forms have not been described in the jejunum and in the ileum. This may be due to the fact that these two segments of the digestive tract, because of their essential functions, are very resistant to infection.
• megappendix
• megacolon => constipation
• megasigmoid
• megarectum
• hypertrophy of the salivary glands (parotid)
• mesenteric and sciatic nerves necrosis due to type II and IV hypersensitivities
• nyctalopia : under bright conditions, the Chagas patients performed comparably to 50 healthy control individuals. But in the dark, 37 of 45 (82%) Chagas patients had trouble seeing with at least one eye, and 19 of 45 (42%) had trouble with both eyes. It turns out that molecular mimicry can also upset the delicate machinery inside retinal cells. Antibodies geared to attack T. cruzi also block rhodopsin, a molecule that converts light into electrical impulses sent to the brain^ref.
Laboratory examinations :
• PCR, Giemsa staining, Machado-Guerreiro complement fixation, xenodiagnosis in Triatominae infected with patient's serum (looking for parasites in stools after 30-60 days)
• ORTHO^®T.cruzi ELISA Test System (source : Ortho-Clinical Diagnostics) is the first blood-screening test for Chagas' disease approved by the FDA for use in the USA
Therapy :
• nifurtimox 8-10 mg/kg/day po qid for 90-120 days or benznidazole 5 mg/kg/day po for 60 days, exachlorocycloesan, allopurinol (?). These long-term therapies are toxic to some patients. TAK-187 is effective at a dose that is both 10 times lower and administered less frequently than that of benznidazole in preventing CCC.
• autologous bone marrow transplantation into the circulation of patients with severe chagasic cardiomyopathy improves cardiac functions of up to 30%, in one case occurring one month after transplantation
Prevention : blood for transfusions can be sterilized by using methylene blue and KMnO₄, then removed by PVA resin.
• Trypanozoon (in some systems of classification, a subgenus of salivarian trypanosomes (Salivaria section), including Trypanosoma evansi, Trypanosoma equinum, and Trypanosoma equiperdum  => replication in upper tract of vector digestive apparatus (metacyclic trypomastigote in salivary glands) => transmission via vector saliva or regurgitated hemolymph)
• Trypanosoma brucei : 3 morphologically indistinguishable subspecies or varieties
Epidemiology : prevalence : 300,000-500,000 people in 36 African countries after the disease was nearly eradicated in the early 1960s; incidence 20,000 / yr ; population exposed at risk : 50 millions (< 20% in medicalized areas). The WHO estimates that trypanosomiasis was almost eradicated from West Africa after 1960 but has been increasing since then, with approximately 500,000 cases annually. Reported cases in recent years are from countries where surveillance coverage is < 5%. In certain villages of many provinces of Angola, the Democratic Republic of Congo and southern Sudan, the prevalence is 20-50%. Sleeping sickness has become the 1st or 2nd greatest cause of mortality, ahead of HIV/AIDS, in those provinces^ref. A study of visceral leishmaniasis, VL, in Kenya diagnosed 904 patients from an area which spanned the Wajir and Mandera districts of northeastern Kenya, southern Somalia, and southeastern Ethiopia. These areas were either previously non-endemic for VL or had only sporadic cases prior to the epidemic. The study describes the features of the outbreak and reviews the history of VL in the region. Unusual rainfall patterns, malnutrition, and migration of a Leishmania-infected population seeking food and security may have contributed to this outbreak^ref. Another study from 2000 of VL in refugees from Somalia entering northeastern Kenya^ref speculates that the deteriorating nutitrional status of the refugees played a role in the increased incidence of VL. The present increase in cases is most probably part of a larger outbreak of the entire region including eastern Ethiopia, Somalia, and northeastern Kenya. Leishmaniasis is a HIV-related infection, and it is important to know the proportion of patients with VL who are also HIV^+ref
Transmission : about 20 species of the tsetse fly are found across 1/3 of the continent in 37 sub-Saharan countries
=> African trypanosomiasis / maladie du sommeil / African sleeping sickness
• Trypanosoma brucei brucei (a.k.a. Trypanosoma brucei) infects mammals, but not humans, being transmitted by various tsetse flies from a reservoir in wild animals, in which it causes a relatively mild infection, to various domestic animals in which it causes a severe, often fatal, disease (nagana), including Bos taurus, Equus caballus, Ovis aries, Capra hircus, Canis familiaris, Sus scrofa, and Camelidae. It may be acute or chronic and its pathogenicity and symptoms are determined by many factors, such as the trypanosome involved and the species infected. Anemia, fever, and emaciation occur in many species, corneal opacities in horses and Canis familiaris, and abortion in cows (enzoonotic, non pathogenetic for Homo)
• Trypanosoma brucei gambiense (a.k.a. Trypanosoma gambiense, Trypanosoma hominis, and Trypanosoma ugandense)
Epidemiology : West and Central Africa; in 2003, 96 Angolans died of sleeping sickness while 3,115 new cases and 270,000 suspected cases were detected nationwide^ref : the previous reports on human trypanosomiasis have been from the area around the town of Uige in the northern parts of Angola, which is still struggling to rebuild  after a 27-year civil war that ended in April 2002. On Feb 2004 the first report of widespread trypanosomiasis in the southern provinces of Kunene, Huambo, Namibe, and Huila. Thus the epidemic seems to be spreading and getting closer to Namibia and Botswana. Trypanosomiasis in Angola is a zoonotic infection with cattle and game (e.g. buffalo) as reservoirs, and control relies on trapping and spraying for the tsetse fly and restricting movement of cattle and game.
Transmission : a zooanthroponosis from Sus scrofa reservoir in bush; vectors : hygrophilic Glossinae (Glossina palpalis, Glossina tachinoides and G. fuscipes: only < 10% is infected)
Laboratory examinations : highly sensitive tests are available for serological screening but the sensitivity of parasitological confirmatory tests remains insufficient and needs to be improved. Recent studies have confirmed the high accuracy of raised IgM levels in the cerebrospinal fluid for the staging of T. b. gambiense HAT, and a promising simple assay (LATEX/IgM) is being tested in the field^ref
=> chronic or Gambian form of trypanosomiasis / Central-Western African sleeping sickness :
• acute phase : 2 stages of illness (trypanosomal chancre or trypanoma (3÷10 cm, 2-7 days after the bite and lasts 2-4 weeks) and meningoencephalitis), anemia, posterior cervical lymphadenitis (Winterbottom sign), facial edema => facies japonica, headache, myoarthralgia, rash for 1 yr
• chronic phase for 4-8 months : meningoencephalitis, lethargy, deep hyperesthesia accompanied by pain, often retarded, after some slight blow upon a bony projection of the body (Kerandel's sign), petechial rash => opportunistic infections => death.
• latency in CNS (?)
• Trypanosoma brucei rhodesiense (a.k.a. Trypanosoma rhodesiense) a polymorphic subspecies
Epidemiology : East Africa.
• Uganda : the epidemic in eastern Uganda, which began in 1998 as a result of movements of the livestock reservoir of the parasite, has continued to spread. An additional 200,000 people have been put at risk of infection in Kaberamaido, another newly affected district. The few resources committed to control interventions in Soroti district have failed to contain the epidemic. The high prevalence of the parasite in cattle presents a significant risk for transmission to human beings and further spread of this neglected zoonotic disease. Targeted interventions are urgently needed to control epidemics and reduce the high mortality resulting from sleeping sickness^ref.
• Malawi : there are 8 human trypanosomiasis-affected districts out of the 25 districts : Rumphi in the northern region; Kasungu, Ntchisi, and Nhotakota in the central region; and Mangochi, Machinga, Chikwawa, and Mulanje in the southern region.
Transmission : a zooanthroponoses from antelope reservoir in savannah (particularly the bushbuck and hartebeest); domestic animals, particularly cattle, may also serve as reservoirs; vectors : xerophilic Glossinae (Glossina morsitans, Glossina pallidipes, Glossina swynnertoni: only < 10% is infected); intrahuman cycles of infection are possible
Laboratory examinations : screening still relies on clinical features in the absence of serological tests available for field use. Ongoing research is opening perspectives for a new generation of field diagnostics. ^ref
=> acute or Rhodesian trypanosomiasis / Eastern African sleeping sickness (, more rapid evolution than above, 3 stages of illness :
• trypanosomal chancre or trypanoma (3÷10 cm, 2-7 days after the bite and lasts 2-4 weeks)
• hemolymphatic
• meningoencephalitis (lethargy)
More severe prognosis than gambian form.
Genomics : > 1 billion years ago the ancestor of trypanosomes probably merged with a type of green algae, enabling it to harness the Sun's energy : the passenger degenerated, and some of its genes passed to those of the trypanosome. The genes' exotic origins should reduce the risk of side effects from therapeuticals targeting them.
Laboratory examinations : direct microscopy of the blood (fresh examination or May-Grumwald and Giemsa staining) and cerebrospinal fluid (Mott cell / mulberry, berry, grape, or morular cells are found in the brain in late stages), antibody analysis (EIA, DASS), and detection of specific DNA; hypoalbuminemia, hypertransaminasemia, anemia, lymphomonocytosis, thrombocytopenia^{ref1, ref2}, DIC^ref. Hyper IgM due to polyclonal B-cell activation, but no Ab immunity due to Ag drift of variable surface glycoprotein (VSG). Also essential for both forms of HAT is accurate determination of the disease stage because of the high toxicity of melarsoprol, the drug most widely used during the neurological stage of the illness, which can kill up to 10% of patients
Treatment :
• arsenic derivatives
• triclosan
• pentamidine isethionate or methylate + suramin sodium + melarsoprol + eflornithine + diminazene. The treatment regimen for melarsoprol varies from country to country, but in Angola, it has, in the recent past, been administered as 3-4 consecutive injections given every 24 hours, with an interval of about a week before the 2nd and 3rd course of injections. Elsewhere, pentamidine has been given as 10 injections on alternate days, or used for 2 days prior to a course of melarsoprol. It is unclear what regimen is currently being used in Angola.
• farnesyl diphosphate synthase (FPPS) inhibitors^ref
Environmental prophylaxis : organochlorinated insecticides; pyrethroid-impregnated attractant traps have been used in many sub-Saharan countries, including Angola, to trap and kill the tsetse flies, as well as ground or aerial applications of mainly pyrethroid insecticides to kill adult tsetse resting on vegetation. But, spraying, especially aerial application, is expensive and needs considerable organization.
Trypanosoma equinum : a salivarian species transmitted mechanically primarily by tabanid flies and causing mal de caderas in horses. Except for the absence of a kinetoplast it is identical with Trypanosomaevansi.

Epidemiology : in Central and South America
Trypanosoma equiperdum (a.k.a. Trypanosoma (Trypanozoon) equiperdum, Trypanosomarougeti) : a salivarian species structurally indistinguishable from T. evansi that causes the venereal disease dourine in horses in Africa, Asia, and certain regions of Europe and North and South America
Trypanosoma evansi (a.k.a. Trypanosoma (Trypanozoon) evansi, Trypanosoma hippicum): a salivarian species transmitted mechanically usually by tabanid flies

Epidemiology : in the Far and Middle East, in North Africa outside of tsetse fly–inhabiting areas, and in certain parts of Central and South America where the vampire bat is also a vector. In the booklet published in 1977 by the Indian Council of Agricultural Research (ICAR), New Delhi, 124 p.: " B.S. Gill: Trypanosomes & Trypanosomiases of Indian Livestock," a very well-documented review on Trypanosoma evansi and T. equiperdum a human laboratory contamination by T. evansi is described that was cured by Atoxyl (arsenical derivative) (p. 36). Unfortunately a reprint of this unique report (published in the C.R. of the French Acad. Sci.,1945) is impossible to obtain. This human case of a so-called human trypanosomiasis in Asia has to be compared with a similar case occurred in Sri Lanka in 1999. At the time of report it was mentioned that a T. evansi like organism was identified but there was no definitive conclusion as to the final identification of the organism. In that incident, the case was a cattle herder with significant exposure to cattle, somewhat "explaining" the possible risk exposures. Perhaps sources in India might have more information on possible sources of contact for the 2 reported cases (Maharashtra and Kolkata), and sources in Sri Lanka might have final information on the 1999 case. Human trypanosomiasis in Africa is transmitted by tsetse flies (Glossina species) and they certainly do not occur in India. Apart from 2 localities in the Arabian peninsular these flies are restricted to sub-Saharan Africa. Other biting flies such as stable flies (Stomoxys spp.) and tabanids have been considered of possibly transmitting human trypanosomes in Africa by purely mechanical means, that is through their contaminated mouthparts. Species of Trypanosoma, such as Trypanosoma evansi, are widely distributed in Central and South America and also Asia and infect domestic and wild animals causing animal trypanosomiasis. In the absence of tsetse flies other biting flies such as tabanids and stable flies are the vectors. But this does not add much in clarifying the recently reported cases of trypanosomes in India, because we still do not know what trypanosome species is involved, but together with a previous report it does help stress that there are many species of trypanosomes, some of which occur outside Africa
=> surra, which is an economically important disease in domestic animals such as camels, equines, cattle, elephants, and dogs.
Laboratory examinations : Dürck's nodes (granulomatous perivascular infiltrations in the cerebral cortex in trypanosomiasis)
Resistance : serum apoL1 / trypanosome lytic factor (TLF) can prevent infection by susceptible trypanosomes but not from strains encoding a truncated form of the variant surface serum resistance associated (SRA) glycoprotein : TLF enters parasited cells via the endocytic pathway but in lysosomes the amino-terminal a-helix of SRA binds the carboxy-terminal a-helix of TLF disabling its lytic function.
• Diplomonadida : an order of mostly parasitic, bilaterally symmetrical protozoa (class Zoomastigophorea, subphylum Mastigophora) having one or two karyomastigonts, each with one to four flagella. It includes two suborders: Diplomonadina and Enteromonadina.
• [Diplomonadina : a suborder of mostly parasitic protozoa (order Diplomonadida, class Zoomastigophorea) having 2 karyomastigonts, each containing four flagella. Representative genera include Giardia, Hexamita, and Trepomonas]
• Hexamitidae
• Giardiinae
• Giardia [Alfred Giard, biologist in Paris, 1846–1908] : a genus of usually nonpathogenic, flagellate intestinal protozoa (suborder Diplomonadina, order Diplomonadida) parasitic in various vertebrates, including humans, characterized by the presence of a large sucking disk on the ventral body surface, by means of which the organism adheres to the microvilli of the host's intestinal epithelium; 2 anterior nuclei; and 8 flagella in 4 pairs.
• Giardia intestinalis (a.k.a. Giardia lamblia, Giardia duodenale, Lamblia intestinalis)
• Giardia lamblia ATCC 50803
Epidemiology : the most common water-borne pathogen identified in USA; and as many as 60% of giardia infections are acquired from water (1987). The organism is present in 7.2% of stools submitted to state laboratories. Highest rates are reported from the Middle Atlantic states. Rates peak in September in all regions. 90 outbreaks (23,500 cases) were registered during 1965 to 1984. 100 water-related outbreaks were reported during 1972 to 1990,  and 5 outbreaks (385 cases) during 1993 to 1994. It is estimated that 4,600 were hospitalized for this disease annually during 1979 to 1988. Norway draws almost all its drinking water from surface sources : a survey of raw water sources in 1998 and 1999 found 9% of samples containing Giardia spp. cysts and 2.5% containing both Giardia and Cryptosporidium cysts (the source of the contamination points to the number of domestic animals within the catchment area of the water reservoirs)^ref. A chronology of significant Giardiasis outbreaks in the USA :
• 1974 to 1975 : an outbreak (350 cases) of waterborne giardiasis was reported in New York State.
• 1975 : outbreaks of giardiasis and shigellosis were reported at a single day care center.
• 1976 (publication year) : an outbreak (34 cases) was reported among campers in Utah.
• 1980 : an outbreak (213 symptomatic cases) of waterborne giardiasis was reported in New Hampshire.
• 1980 : an outbreak (780 cases) of waterborne giardiasis was reported in Montana.
• 1981 : an outbreak of waterborne giardiasis was reported at a ski resort in Colorado.
• 1982 : an outbreak (324 cases) of waterborne giardiasis was reported in Nevada.
• 1983 to 1984 : outbreaks (3 outbreaks) occurred at a single child day care center in Wisconsin.
• 1985 : an outbreak (9 cases) was associated with a swimming pool in New Jersey.
• 1986 : an outbreak (88 cases) was reported at a nursing home in Minnesota.
• 1988 : an outbreak (22 cases) in New Mexico was ascribed to taco ingredients.
• 1990 (publication year) : an outbreak (9 cases) was related to fruit salad which had been contaminated by a food handler.
• 1995 : an outbreak (1449 cases) in New York State was related to lake water.
• 1996 : an outbreak (77 cases) in Florida was ascribed to pool water.
• 1997 : outbreaks (150 cases, total) associated with drinking water were reported: New York (50 cases) and Oregon (100 cases).
• 1998 : outbreaks (9 cases in 2 outbreaks) associated with water were reported in Florida.
• 2003 : an outbreak (97 cases and 105 secondary cases) was reported in Boston.
• 2004 : an outbreak (1450 cases) of waterborne infection on a residential island in Ohio included infections by Norovirus, Salmonella, Campylobacter and Giardia.
There are multiple genotypes of Giardia spp., which infects humans, domestic animals and wildlife worldwide, and Giardia spp.
is endemic in fresh water in the USA. New molecular typing has made it possible to start mapping infection within and between species^ref. Drinking water is an important route of transmission, but other routes such as contaminated food play a role in some of the outbreaks
Genomics : Giardia lamblia genome project ; homologs of 5 genes specific to meiosis in animals, fungi, and plants are present in Giardia—Dmc1 promotes interhomolog recombination; Spo11 creates DNA double-strand breaks; Hop1 is part of the synaptonemal complex; and Hop2 and Mnd1 ensure accurate and efficient homology searching. Of the meiotic genes surveyed, Giardia does not appear to encode Rad51, nor mutS homologs Msh4 and Msh5, which comprise core meiotic recombination machinery^ref, along with Dmc1, Spo11, Rad50/Mre11, and Mlh1, which Giardia does possess. Entamoeba histolytica and Encephalitozoon cuniculi, neither of which are known to undergo meiosis, contain some meiotic-specific genes found in Giardia, suggesting hidden sex lives might be present in those species as well^ref.
Transmission : direct or indirect oro-faecal route (expecially in babies) : ingestion of human faeces (contaminated water or food, coprophagy, anilingus) or water contaminated by feces of cat, Canis familiaris or beavers (infection is characterized by copious diarrhea and anorexia; it may be persistent or self-limiting). The evidence does not, in general, support zoonotic transmission as a major risk for human infections^ref
=> giardiasis / lambliasis / lambliosis : many infected persons are asymptomatic, while others after 1-3 weeks incubation experience diarrhea (continuous or intermittent for 5-7 days), steatorrhoea, abdominal pain, nausea and vomiting, anorexia, flatulence, fatigue and weight loss due to malabsorption. The acute phase may last days or weeks, with resolution usually spontaneous. Some patients develop chronic giardiasis, which persists for many years causing malabsorption, dyspepsia and abdominal pain.
Laboratory examiantions : Enterotest (string test). Metronidazole 250 mg. tid x 5 days is a common treatment. Alternatives include furazolidone, albendazole, and paromomycin.
Prevention : Giardia is more susceptible to chlorination than Cryptosporidium
Web resources : MED-VET-NET : The Giardia Cryptosporidium databases at The RIVM Epidemiological and Molecular typing Electronic Data InfraStructure
• Parabasalidea
• Trichomonadida : an order of chiefly parasitic protozoa (superorder Parabasalidea, class Zoomastigophora), typically characterized by the presence of karyomastigonts with 4-6 flagella, one of which is recurrent or free or has a proximal segment or the entire length adherent to the body surface; an undulating membrane (if present) associated with adherent segments of recurrent flagellum; and a pelta and noncontractile axostyle in each mastigont. Representative genera include Dientamoeba, Histomonas, Monocercomonas, and Trichomonas.
• Trichomonadidae
• Trichomonadinae parasitic flagellated protozoa of the order Trichomonadida, class Zoomastigophorea, found in the intestinal and genitourinary tracts of various invertebrates and vertebrates, including humans, and characterized by the presence of a pelta, an axostyle, an undulating membrane, and 3-5 anterior flagella
• Tritrichomonas with 3 flagella
• Trichomonas foetus : found in the genital tract of cattle; it causes a contagious venereal disease (bovine trichomoniasis) transmitted from bulls to cows by coitus or by artificial insemination, and characterized by early abortion, pyometra, and sterility.
• Trichomonas with 4 flagella
• Trichomonas gallinae : found in the upper digestive tract and associated structures and in other organs, especially the liver, of domestic pigeons and various other birds, in which it causes a form of avian trichomoniasis (necrotic lesions of the upper digestive tract). Infection varies from mild to a rapidly fatal disease manifested by caseous accumulations and necrosis in involved tissues and severe weight loss.
• Trichomonas gallinarum : found in the lower digestive tract of chickens, turkeys, and other domestic birds in which it sometimes causes a fatal form of avian trichomoniasis (necrotic lesions of the upper digestive tract). Infection is manifested by lesions of the cecum and liver, diarrhea, and loss of appetite and weight.
• Trichomonas tenax (a.k.a. Trichomonas buccalis) a commensal species found in the mouth of primates, including humans, where it is most often seen in the tartar around teeth, cavities of carious teeth, pockets associated with periodontal disease, and tonsillar crypts
• Trichomonas vaginalis : an anaerobic species found in the vagina and male genital tract
Epidemiology : is of particular interest in North America because it is the most prevalent parasite on the continent, where it infects 5 million people each year
Transmission : no cyst stage => only direct transmission by sexual route (> 15% females)
=> trichomoniasis or trichomoniosis vaginalis, seen in both females and males. The symptomatic condition in females (competing for glycogen with Lactobacillus acidophilus=> vagina pH increases over 6 => opportunistic infections => 25-50% all nongonococcal urethritis (NGUs) and vulvovaginitis (including bartholinitis)) may take the form of a severe vaginitis associated with discharge, burning, pruritus, and chafing; in males it is seldom symptomatic and may rarely produce nongonococcal urethritis (NGUs), prostatitis, and epididymitis.
Therapy : for both partners
• Pentatrichomonas with 5 flagella
• Pentatrichomonas hominis (a.k.a. Trichomonas hominis and Trichomonas intestinalis) is one of the most common enteric flagellates seen in humans, in whom it may be present in large numbers but is generally considered to be nonpathogenic
• => commensal in caecum and colon => gastroenteritis, intermittent mucous diarrhea, anorexia, abdominal pain
• Monocercomonadidae
• Dientamoeba : a genus of small highly active, usually nonpathogenic or mildly pathogenic ameboid protozoa (superorder Parabasalidea, order Trichomonadida) parasitic in the large intestine of humans and certain monkeys, and typically characterized by the presence of two nuclei connected by a desmose and an endosome formed by 4-8 chromatin granules
• Dientamoeba fragilis

Epidemiology : the organism is identified in 0.5% of stool specimens submitted to USA state laboratories. California accounts for 55.8% of reports.
Transmission : vector : Enterobius vermicularisnematode
=> commensal in caecum and colon => gastroenteritis, intermittent bloody, mucoid or loose diarrhoea, anorexia, abdominal pain, and flatulence
• Entamoebidae
• Endolimax
• Endolimax nana
=> commensal in caecum and colon : non pathogenic ?
• Entamoeba : a genus of naked ameboid protozoa (suborder Tubulina, order Amoebida) parasitic in invertebrates and vertebrates, including humans, and characterized by the presence of a vesicular nucleus with a comparatively small central karyosome with a number of peripheral chromatin granules attached to the nuclear membrane.
• Entamoeba coli
Shape is similar to that of Entamoeba histolytica, except for the 8 nuclei in the cyst.
=> commensal in human caecum and colon : non-pathogenic ?
• Entamoeba dispar

species virtually identical to E.hystolytica but nonpathogenic: differentiated by zymodemes.
=> commensal in colon : non-pathogenic ?
• Entamoeba gingivalis (a.k.a. Entamoeba buccalis)
=> often found in the oral cavity of humans with periodontal disease; non-pathogenic ?
• Entamoeba hartmanni

found in the human intestinal tract ; almost indistinguishable from but smaller than E. histolytica; it was formerly designated “small race” E. histolytica.
=> commensal in colon : non-pathogenic ?
• Entamoeba histolytica
Epidemiology :
• USA : the parasite infects an estimated 50 million people and causes as many as 100,000 deaths a year -- second only to malaria as a cause of morbidity and mortality from a protist.
• a massive outbreak occurred in Chicago in 1933 with 1,409 cases (98 fatal). 147,975 cases were reported during 1944 to 1983 (mean 3,699/year); 2,989 in 1991 (1,419 of these from California); 2,942 in 1992; 2,970 in 1993 (1,193 from California); 2,983 in 1994 (991 from California).
• fatal cases decreased from 614 during 1961 to 1970, to 86 during 1982 to 1991. 28 fatalities below age 5 were registered during 1968 to 1991.
• the parasite is identified in 0.9% of stool specimens submitted to state laboratories. The estimated true prevalence for the general population is 4%.
Previous reported outbreaks of amoebiasis :
• 1933 : an outbreak (1408 cases, 98 fatal) of amoebiasis was reported in Chicago.
• 1978 to 1980 : an outbreak (36 or more cases) of amoebiasis in Colorado was related to colonic irrigation at a chiropractic clinic
• 1984 (publication year) : an outbreak of amoebiasis on an Israeli kibbutz affected 25 per cent of the population.
• 1992 (publication year) : outbreaks of giardiasis and amoebiasis were reported among Italian tourists staying at a hotel in Phuket, Thailand.
• 1993 : an outbreak (207 cases) of combined amoebic and bacillary dysentery was reported in Taichung, Taiwan.
• 1997 to 1998 : an outbreak (298 cases) of bloody diarrhea due to Escherichia coli O157, Shigella and amoebiasis was reported in the Dja River region, Cameroon.
• 1998 : an outbreak (53 cases of intestinal amoebiasis and 37 of amoebic abscess) was reported in Tbilisi, Georgia; drinking water was suspected as the source of the outbreak. It was estimated at the time that 84 000 to 225 000 persons may have been infected. 10 per cent of healthy controls in the region were seropositive at the time; and 3 per cent were seropositive 6 months later.
• 1998 : an outbreak (464 cases) was reported in Taegu, Republic of Korea.
• 2002 : an outbreak (216 cases) among Spanish tourists in Punta Cana, Dominican Republic was ascribed to contaminated water.
• 2004 (publication year) : an outbreak (3 cases, including one hepatic
abscess) of presumed autochthonous amoebiasis was reported in a Dutch family
Genomics : Entamoeba histolytica Genome Project reveals a variety of metabolic adaptations shared with two other amitochondrial protist pathogens: Giardia lamblia and Trichomonas vaginalis. These adaptations include reduction or elimination of most mitochondrial metabolic pathways and the use of oxidative stress enzymes generally associated with anaerobic prokaryotes. Phylogenomic analysis identifies evidence for lateral gene transfer of bacterial genes into the E. histolytica genome, the effects of which centre on expanding aspects of E. histolytica's metabolic repertoire. The presence of these genes and the potential for novel metabolic pathways in E. histolytica may allow for the development of new chemotherapeutic agents. The genome encodes a large number of novel receptor kinases and contains expansions of a variety of gene families, including those associated with virulence. Additional genome features include an abundance of tandemly repeated tRNA-containing arrays (10%), which may have a structural function in the genome^ref
Proteomics : it produces a p14^{pore forming protein (PFP)}. Shape is similar to that of Entamoeba coli, except for the 4 nuclei in the cyst.
Transmission : oro-faecal route from ingestion of cysts in contaminated food (raw vegetables, sugar-based foods) and water (ice-containing products)
=> intestinal amebiasis :
• asymptomatic
• non-invasive symptomatic amebiasis : chronic intermittent diarrhea, abdominal pain
• fulminant colitis in immunocompromised hosts and pregnants : peritonitis
• toxic megacolon (0.5%)
• acute rectocolitis or acute amoebic dysentery after 2 days-some months incubation : anorexia => meteorism, diarrhea=> cardiocirculatory shock, "button-shaped" or "flask-shaped" ulcers in caecum and colon (=> perforation (2-7%) => amoebic peritonitis) and direct extension to skin (cutaneous amebiasis) ; hematogenous spread causes invasive or extraintestinal amebiasis : amebic abscess(es) (ameboma) is right lobe liver abscess (symptoms after weeks or months), spleen, lungs (pleuritis, pneumonia), brain, heart (pericarditis) and genitalia.
• chronic intestinal amebiasis or non-dysenteric chronic colitis (similar to IBDs) => stenosating scars in colon, ameboma (0.5-1%) in caecum or abscending colon.
Laboratory examinations : Anderson's phenomenon : clumps of red blood cells in the feces, seen on microscopic examination in amebic dysentery.
Chemotherapy : metronidazole, nimorazole, tinidazole and ornidazole ; colonization without symptoms is treated with paromomycin or iodoquinol.
• Entamoeba invadens :  the only pathogenic species of the genus Entamoeba other than E. histolytica, producing lesions of the stomach, colon, duodenum, ileum, colon, and liver in reptiles.
• Entamoeba polecki : an intestinal parasite of hogs, sheep, monkeys, cattle, and occasionally humans.

=> commensal in colon : non-pathogenic ?
• Alveolata
• Apicomplexa / Sporozoa : a phylum of uninucleate, parasitic tissue-dwelling protozoa characterized by the presence of an apical complex; one or more micropores are generally present at some stage of development. Flagella and cilia are absent in the adult stage; many mature apicomplexans glide by means of ultrastructural ridges and fibers on the body surface. They typically reproduce asexually by means of multiple fission, forming merozoites or schizoites, or by endodyogeny, or sexually by syngamy. These parasites contain a relict plastid-termed "apicoplast"--that originated from the engulfment of an organism of the red algal lineage. The apicoplast is indispensable but its exact role in parasites is unknown. The apicoplast has its own genome and expresses a small number of genes, but the vast majority of the apicoplast proteome is encoded in the nuclear genome. The products of these nuclear genes are posttranslationally targeted to the organelle via the secretory pathway courtesy of a bipartite N-terminal leader sequence. Apicoplasts are nonphotosynthetic but retain other typical plastid functions such as fatty acid, isoprenoid and heme synthesis, and products of these pathways might be exported from the apicoplast for use by the parasite. Apicoplast pathways are essentially prokaryotic and therefore excellent drug targets. Host-cell invasion by apicomplexan parasites involves the successive exocytosis of 3 different apical secretory organelles :
• micronemes are apparently used for host-cell recognition, binding, and possibly motilitymicroneme proteins containing thrombospondin-like domains, which are likely to be involved in binding to sulphated glycoconjugates. These molecules have been shown to be shed on the parasite and/or cell surfaces during the invasion process in Plasmodium, Toxoplasma and Eimeria.
• rhoptries for parasitophorous vacuole formation
• dense granules for remodeling the vacuole into a metabolically active compartment
It comprises 2 classes: Perkinsea and Sporozoea
• Coccidia
• Eimeriida [Eucoccidiida : an order of parasitic protozoa found in the blood and epithelial cells of invertebrates and vertebrates, and having a life cycle involving merogony. Human pathogens are included in the suborders Eimeriina and Haemosporina]
• Eimeriidae (a.k.a. Sporozoea) [Eimeriina : a suborder of homoxenous or heteroxenous protozoa, usually parasitizing the gut epithelium of the host, in which the macrogamete and microgametocyte develop independently, syzygy does not occur, the microgametocyte gives rise to numerous biflagellated microgametes, the zygont is not mobile, and the sporozoites are typically enclosed in an oocyst. Representative genera include
• Aggregata : a genus of coccidian protozoa, the life cycle of which involves schizogony in a crustacean and sporogony and gametogony in a cephalopod.
• Besnoitia
• Cryptosporidium
• Eimeria
• Isospora
• Sarcocystis
• Toxoplasma
• Tyzzeria]
• Cyclospora : genus of coccidian protozoa characterized by the presence of 2 sporocysts in each oocyst, which is covered by a bivalve shell, and two sporozoites in each sporocyst
• Cyclospora cayetanensis (a.k.a. cyanobacterium-like or coccidia-like body (CLB))
Epidemiology : first human case reported in 1979; endemic in many developing countries (Guatemala, Nepal^ref, Peru^ref)
Transmission : fecal-oral route : Cyclospora oocysts needs days or week after being passed in a bowel movement to sporulate and become infectious. Therefore, it is unlikely that Cyclospora is passed directly from one person to another. It is unknown whether animals can be infected and pass infection to people. Ingestion of oocysts attached to^{ref1, ref2} :
• blueberries
• Guatemalan raspberry (e.g. garnish served on top of a strawberry dessert) : outbreak in North America in ...
• 1990 : an outbreak in Chicago affected 17 physicians and 3 hospital employees, and was traced to contaminated drinking water
• 1995
• May-June 1996 (1,270 cases in > 15 states, District of Columbia and the Canadian province of Ontario : (978 laboratory-confirmed in the United Sates - including New York 307, Florida 220, Massachusetts 170, New Jersey 103) : raspberries are thought to have been contaminated by water used in irrigation and pesticide sprays
• March-April 1997 : an outbreak involved 220 clinical cases (4 of these laboratory confirmed)
• April-June 1997 : 21 event-associated case clusters were reported from 8 states (California, Florida, Maryland, Nebraska, Nevada, Rhode Island, New York [includes 20 cases out of 160 guests at an April wedding Westchester County] and Texas) and Canada (300 people in southern Ontario), and involved approximately 370 clinical cases (140 of these laboratory-confirmed). Fresh raspberries, imported from Guatemala, had been served in 19 of the 21 outbreaks. An additional 70 sporadic laboratory-confirmed sporadic cases were reported for the United States and Canada during this period. A report of 8 cases among 62 Canadian passengers who, during March 29-April 5, had been on a cruise ship that left from Florida. Also Maryland, Nebraska and Rhode Island. The most recent of the 8 events occurred on May 8. Approximately 90 event-associated cases of infection have been laboratory confirmed. Fresh berries were served at 6 of the 8 events. Raspberries were included in mixtures of various types of berries at 4 events, were served separately from other berries at one event (the event in Westchester County), and were the only type of berry served at one event (in Nevada). At one event where the implicated food item included a mixture of berries, the source of the raspberries was Guatemala; preliminary trace-back data for the other events at which raspberries were served indicate that both Guatemala and Chile may be sources (i.e., each country was the source of at least one of the shipments of raspberries that could have been used). The USA temporarily banned imports of Guatemalan raspberries : the crisis forced growers to close > 30 Guatemalan farms of an industry that once employed up to 6000 people.
• 1998 : 2,500 cases in USA; > 305 in Canada, associated with raspberries from Guatemala => a ban on import was placed there as well. Medical experts thought 1998 outbreak occurred because the raspberries were harvested during Guatemala's rainy season, when that country suffers a flulike "May sickness," but in 1999 farmers harvested their berries before the rainy season, yet cyclospora struck again
• 1999
• June 10, 2000 (57 attendees of a wedding reception held in Philadelphia)
• raw fresh basil (e.g. in pesto) : 26 clusters (239 cases) were reported during June to July 1997 from Virginia, Washington DC and Baltimore; 300 cases in Florida in 2005
• mesclun lettuce
• spring mix salad : 57 people in Wheaton, Illinois reported getting sick in February 2004 after eating food containing basil and mesclun, or spring salad mix, at a restaurant. So far, lab tests have confirmed that 20 of those cases were cyclosporiasis. Also in February 2004, 38 people in Irving, Texas, also reported that they got sick after eating basil and mesclun at a local restaurant. Tests have confirmed that 16 of those were cyclosporiasis
• raw Guatemalan snow peas in pasta salad at 5 special events from late May through late June 2004 in Pennsylvania : approximately 50 potential cases^ref
• May 10-16, 1999 : > 200 cases out of 274 guests from 28 states at American General Life Brokerage Group's convention, West Palm Beach
Pathogenesis : infects the small intestine
after few days-1 week incubation => cyclosporiasis : prolonged watery diarrhea with frequent, sometimes explosive bowel movements for 1-8 weeks, seen especially in immunocompromised patients. Other symptoms include loss of appetite, substantial loss of weight, bloating, increased gas, stomach cramps, nausea, vomiting, muscle aches, low-grade fever and fatigue. If untreated, illness may last for a few days to a month or longer, and symptoms may follow a remitting-relapsing course. Some people who are infected with Cyclospora do not have any symptoms.
Reinfection can occur.
Laboratory examinations : Cyclospora like Cryptosporidium is positive in the Sheathers sugar solution.
• to maximize recovery of Cyclospora oocysts, first concentrate the stool specimen by the formalin-ethyl acetate technique (centrifuge for 10 minutes at 500 x g) and then examine a wet mount and/or a stained slide of the sediment.
• Cyclospora oocysts are 8-10 mm in diameter (in contrast, Cryptosporidium parvum oocysts are 4-6 mm in diameter).
• ultraviolet epifluorescence microscopy is a sensitive technique for rapidly examining stool sediments for Cyclospora oocysts, which autofluoresce (Cryptosporidium parvum oocysts do not). If suspect oocysts are found, bright-field microscopy can then be used to confirm that the structures have the characteristic morphologic features of Cyclospora oocysts (i.e., are nonrefractile spheres that contain undifferentiated cytoplasm or refractile globules)
• on a modified acid fast-stained slide of stool (the technique used by most laboratorians), Cyclospora oocysts are variably acid fast (i.e., in the same field, oocysts may be unstained or stain from light pink to deep red). Unstained oocysts may have a wrinkled appearance; it is important to distinguish oocysts from artifacts that may be acid fast but do not have the all-important wrinkled morphology of the oocyst wall
• using a modified safranin technique, oocysts uniformly stain a brilliant reddish orange if fecal smears are heated in a microwave oven during staining. If epifluorescence microscopy is available, the stained slide can first be examined with this technique and suspect oocysts reexamined with bright-field microscopy
• although not recommended as an optimal technique for detection of Cyclospora, on a trichrome-stained slide of stool, the oocysts appear as clear, round, and somewhat wrinkled spheres ("golf ball"), either 8-10 mm in diameter or slightly smaller because of shrinkage during the staining process.
Therapy : cotrimoxazole^ref (adults should receive TMP 160 mg plus SMX 800 mg (one double-strength tablet) orally twice a day for 7 days. Children should receive TMP 5 mg/kg plus SMX 25 mg/kg twice a day for 7 days. Patients with AIDS may need higher doses and long-term maintenance treatment). No alternative antibiotic regimen has been identified yet for patients who do not respond to or are intolerant of TMP/SMX. Anecdotal or unpublished data suggest that the following drugs are ineffective: albendazole, trimethoprim, azithromycin, nalidixic acid, norfloxacin, ciprofloxacin, tinidazole, metronidazole, quinacrine, tetracycline, doxycycline, and diloxanide furoate. Approaches to consider for treatment of such patients include observation and symptomatic treatment, use of an antibiotic whose effectiveness against Cyclospora is unknown or is based on limited data, or desensitization to TMP/SMX. The latter approach should be considered only for selected patients who require treatment, have been evaluated by an allergist, and do not have a life-threatening allergy.
Prevention :
• because raspberries are fragile and replete with crevices, even thorough washing may not eliminate contamination of the fruit
• irradiation of vegetables and fruits
• Eimeria [Gustav Heinrich Theodor Eimer, German zoologist, 1843–1898]  a genus of homoxenous coccidian protozoa (suborder Eimeriina, order Eucoccidiida) found principally as parasites of the gastrointestinal tract of birds and herbivorous mammals but not humans, characterized by the presence of 4 spores in each oocyst and two sporozoites in each spore, the oocysts being passed in the feces. It comprises numerous species, many of which are of economic importance. Some of the common pathogenic species found in domestic animals are
• E. bovis, E. ellipsoidalis, and E. zuernii in cattle
• E. arloingi A (ovina), E. weybridgensis (E. arloingi B), E. crandallis, E. ahsata, E. ovinoidalis, and E. gilruthi in sheep
• E. debliecki, E. scabra, and E. perminuta in swine
• E. leukarti in horses and donkeys
• E. arloingi, E. faurei, E. caprina, and E. ninakohlyakimovae in goats
• E. magna, E. stieda, E. sciurorum, and E. perforans in rabbits
• E. acervulina, E. maxima, E. meleagridis, E. necatrix, and E. tenella in poultry
• Isospora : a genus of coccidian protozoa (suborder Eimeriina, order Eucoccidiida) characterized by the presence of 2 sporocysts in each oocyst and 4 sporozoites in each sporocyst; found in birds, amphibians, reptiles, and mammals, including humans.
• Isospora belli
• Isospora lacazei : a species causing intestinal coccidiosis in passerine birds.
• Isospora suis : a species that may cause coccidiosis in swine.
After intracellular schizogony, telomerozoites become gametocytes => oocysts.
Transmission : oral route (reservoir : Canis familiaris)
=> isosporiasis / coccidiosis : after 1 week incubation : often asymptomatic and is found only upon testing of a stool sample, but occasionally it causes fever, myalgia, and a severe watery mucous diarrhea and steatorrhoea. Self-limiting ; chronicle in immunodepressions
Cystoisospora : a genus of coccidian protozoa that infect the intestines of dogs and cats; formerly classified as part of Isospora. Infections may be subclinical or may lead to mild coccidiosis. C. felis and C. rivolta infect cats. C. burrowsi, C. canis, C. neorivolta, and C. ohioensis infect dogs
• Sarcocystidae
• Sarcocystis : a genus of coccidian protozoa that are parasitic in birds, reptiles, and many mammalian species, including humans and occur as elongated cylindrical bodies (sarcocysts) in the host's muscles. They have an obligatory 2-host life cycle, with sexual reproduction in the definitive host (a carnivore) and asexual reproduction, including schizogony and sarcocyst formation, in the intermediate host. Infection is transmitted by ingestion of the sporocysts in the feces passed by infected animals
• Sarcocystis hominis (a.k.a. Sarcocystis bovihominis and Isospora hominis), formerly considered to be a single genus
• Sarcocystis bovihominis : a species for which cattle are the specific intermediate hosts and humans the definitive hosts; it causes intestinal sarcocystosis in the latter
• Sarcocystis suihominis : a species for which swine are the specific intermediate hosts and humans the definitive hosts; it causes intestinal sarcocystosis in the latter
• Sarcocystis lindemanni : a species causing human infection, most cases of which are asymptomatic, although it may cause polymyositis sometimes associated with eosinophilia.
• Sarcocystis suihominis
They form elongated, fusiform, cylindrical, membrane-bound hyaline bodies (Miescher's bodies, tubes or tubules / Rainey's tube or tubule / sarcosporidian cysts / sarcocysts / zoitcysts) containing the numerous crescentic or banana-shaped, uninucleate trophozoites (Rainey's corpuscles) into parasitophoric vacuoles of RES cells and  : they consist of metrocytes that evolve (through the formation of rhoptries) to bradyzoites / cystozoites.
Transmission : a zoonosis from eating of raw or undercooked beef or pork containing sporocysts of the parasites or by ingestion of sporocysts from the feces of an infected animal, usually in contaminated soil
=> sarcosporidiosis / sarcocystosis / sarcosporidiasis. Heavy infections in cattle and other animals may be associated with anorexia, emaciation, fever, nervousness, lameness, hypersalivation, anemia, and abortion. In humans :
• usually asymptomatic
• muscle cysts associated with myositis or myocarditis
• intestinal infection : anorexia, nausea and vomiting, abdominal pain, diarrhea
• Toxoplasma : a genus of coccidian protozoa) comprising intracellular parasites of many organs and tissues of birds and mammals, including humans. The only known complete hosts are cats and other Felidae, in which both asexual and sexual developmental cycles occur in the intestinal epithelium, culminating in the passage of oocysts in the feces. The intestinal stages do not occur in other hosts.
• Toxoplasma gondii : an obligate intracellular species found in a wide range of hosts, including humans and other mammals and birds. The sexual cycle of the organism takes place in the intestinal epithelium of the cat, which is the definitive host. It exists in 3 forms: tachyzoite, tissue cysts (pseudocysts), and oocysts. Infection (see toxoplasmosis) occurs chiefly by ingestion of oocytes shed in cat feces or by ingestion of cysts in raw or uncooked meat.
Epidemiology : prevalence : 30-80%.
Proteomics : cyclophilin (peptidyl prolyl isomerase) C18 (the active ingredient of soluble tachyzoite antigen (STAg)) is a CCR5 agonist which rapidly induces IL-12 production by DCs, which in turn triggers a T_h1 response that controls the acute infection but then subsides, allowing the maintenance of inactive parasites in tissue cysts, often for the life of the host.
Transmission : intermediate hosts : all homeothermal mammals (expecially Felis catus) and Aves spp.; definitive hosts : Leopardus pardalis, Puma concolor, Prionailurus bengalensis, Felis yagouaroundi, Lynx rufus; vector : Toxocara mystax nematode
• tachyzoites in blood
• tissue cysts in infected meat
• oro-faecal route : schizogony and gametogony in reservoir gut => trophozoite in faeces (inactivable by gastric juice) => (schizogony => merozoites)_n=> oocysts => 2 sporocysts (each containing 4 sporozoites) per oocyst form when it is released in environment => ingestion of oocysts (in water or food contaminated by stools of definitive hosts) or of terminal cysts (in raw meat from intemediate hosts)
• direct exposure to feces
• contaminated soil
The effect of Toxoplasma gondii on neophobic behaviour (the avoidance of novel stimuli) was assessed in 4 groups of wild rats with naturally occurring Toxoplasma infection. 2 groups were placed in individual cages and tested in a series of experiments which examined the effect of Toxoplasma on the rat's reaction to 3 food-related novel stimuli (odour, food-container, food). A trappability study was performed on the other 2 groups to test whether Toxoplasma had an effect on probability of capture. The results show that low neophobia was significantly associated with positive Toxoplasma titres in 3 out of 4 groups. Differences between infected and uninfected wild rats arise from pathological changes caused by Toxoplasma cysts in the brains of infected rats. Such behavioural changes may be selectively advantageous for the parasite as they may render Toxoplasma-infected rats more susceptible to predation by domestic cats (the definitive host of Toxoplasma) and, as a side-effect, more susceptible to trapping and poisoning during post control programmes^ref.
=> toxoplasmosis : sporozoites are phagocytated by RES cells, where they prevent fusion between phagosome and lysosome : so they can be vehicled throughout the body as tachyzoites / endozoites (~ merozoite) in intracellular pseudocysts. Up to 8-16 tachizoites per parasitophoric vacuole can accumulate, thus lysing the RES cell and infecting new cells.
• acute phase
• in immunocompetent hosts : asymptomatic
• in immunocompromised patient : Piringer-Kuchinka cervical and axillary lymphadenitis), myalgia, fever, toxoplasmic meningoencephalitis, bronchopneumonia or interstitial pneumonia (pulmonary toxoplasmosis), acute hepatitis, acute myocarditis, rash, non-lymphocytic leukocytosis. Often lethal.
If a pregnant is infected within month 3 of pregnancy, transplacental infection may cause congenital toxoplasmosis in foetus :
• subacute-chronic : periventricular necrosis and vasculitis, cerebral calcifications (=> dementia), ocular toxoplasmosis / toxoplasmic chorioretinitis and hydrocephalus (3% of infected newborns)
• acute generalized visceral : thrombocytopenia (=> hemorrhages), splenomegaly, hepatomegaly (=> jaundice), interstitial pneumonia (pulmonary toxoplasmosis), maculopapular exanthema.
• mild variety : ocular toxoplasmosis / toxoplasmic chorioretinitis, microphthalmia
No transmission by breast-feeding.
• chronic (latent or asymptomatic) stage : when immune response slows down replication rate, tachizoites can no more lyse cell and so they accumulate (type IV hypersensitivity) as bradizoites / cystozoites in terminal pseudocysts / tissue cyst (perhaps containing thousands of organisms, enclosed by an irregular wall, and representing a resting stage, as opposed to the active, motile stage (tachyzoite); pseudocysts are found in the tissues, especially skeletal muscles, cardiomyocytes, eye and the brain
• reactivation of chronic infection : as intracellular terminal cysts can't be reached by Abs, they can reactivate themselves
• in immunocompetent hosts : acute chorioretinitis
• in immunocompromised hosts : brain abscess (neurotoxoplasmosis : encephalitis), heart abscess, lung abscess and eye abscess.
Laboratory examinations :
• Sabin-Feldman dye test, IFA, ELISA
• brain MRI : multiple ring-enhancing lesions with surrounding oedema and mass effect
• response to antitoxoplasmic therapy, which is usually observed within the first 2 weeks, is also used for diagnostic purposes
Differential diagnosis : Sabin-Feldman syndrome : chorioretinitis and cerebral calcifications, similar to the manifestations of toxoplasmosis, but having all tests for toxoplasmosis negative.
Chemotherapy : pyrimethamine, cotrimoxazole and sulfonamides.
• Cryptosporidiidae
• Cryptosporidium : a genus of minute homoxenous coccidian protozoa, characterized by the presence of oocysts with 4 sporozoites; they are parasitic in the intestinal tracts of many different vertebrates, including humans, causing cryptosporidiosis.  Resist to chlorine in water.
• Cryptosporidium coccidi

=> cryptosporidiosis
• Cryptosporidium muris
=> cryptosporidiosisin gastric glands => gastroenteritis self-limiting within 1-2 weeks, complicating in immunodepressions.
• Cryptosporidium hominis
Epidemiology : infections with cryptosporidia have been extensively reported from the UK. The prevalence -- at least of symptomatic infections -- is low in humans in Scandinavia. Outbreaks of cryptosporidium infections are uncommon in Denmark : in 1989 a nosocomial outbreak involved AIDS patients, where the likely source of the outbreak was an ice cube machine contaminated by a patient excreting the parasite^ref; in August 2005 an outbreak involved 38 employees at a large private company^ref. Serving raw carrots in a bowl of water is common practice, but apparently carries a small risk if people serve the carrots with their fingers. The investigation of cases and controls by questionnaire or interview shows the strength of these methods for identifying the source of infection
Genomics : 8-chromosome 9.2-million-base genome^ref
Proteomics : energy metabolism is largely from glycolysis. Both aerobic and anaerobic metabolisms are available, the former requiring an alternative electron transport system in a simplified mitochondrion. Biosynthesis capabilities are limited, explaining an extensive array of transporters. Evidence of an apicoplast is absent, but genes associated with apical complex organelles are present.
Transmission : restricted to humans
• Cryptosporidium parvum^ref

Epidemiology : worldwide distribution; 70% are children.
• USA :
• in March and April 1993, a major outbreak due to contamination of the public water supply in Milwaukee infected 403,000 people (4,400 hospitalized)^ref, including about half of Milwaukee's residents with AIDS, nearly 70% of whom died within 6 months^ref - this was the largest American waterborne disease outbreak ever described..
• 4 additional outbreaks were registered during 1993 to 1994, involving 271 cases. 2,361 cases were reported (not all states report) in 1996; 581 first half of 1997.
• in May 2001, an outbreak sickened thousands of people in North Battleford, Sask., who drank tainted water
• the parasite is identified in 0.5% of stool specimens submitted to state laboratories, and 65% to 97% of surface water sampled nationwide
• Africa : studies from South Africa have found cryptosporidium in 4-6% of stool samples from children^{ref1, ref2}.
Proteomics : it lacks an apicoplast^ref and there is no mitochondrial genome at all in this parasite (however, a few mitochondrial-associated proteins have been found in the nuclear genome, suggesting the presence of highly degenerate mitochondria in this parasite)^ref, and that is why it has thus far has proved extraordinarily refractory to classical treatments. Biosynthesis is reduced to practically nothing : they completely depend on salvage for most of the molecules they use. This should make them vulnerable to drugs that destroy the parasites' scavenging systems, and Striepen is currently working to disable the enzymes that import nucleotides into the organism with the IMPDH inhibitors ribavirin and mycophenolic acid^ref.
Transmission : a zooanthroponosis : reservoir : Bos taurus => drinking water infected with calf feces containing cryptosporidium cysts; easily passed in swimming pools, where "fecal accidents" from swimmers continuously risk introducing new parasites; it is able to survive outside the body for long periods of time and is resistant to chlorine disinfection
=> cryptosporidiosis in small bowels :
• asymptomatic carriers
• gastroenteritis (including "traveller's diarrhea") expecially in babies with age 1-5 ; loose or watery stool (up to 25 movements per die), stomach cramps, upset stomach, and a slight fever; self-limiting within 1-2 weeks; in immunocompromised patients it is much more serious, manifested as prolonged debilitating diarrhea, weight loss, fever, and abdominal pain, with occasional spread to the trachea and bronchial tree, and sometimes fatal.
It is considered by CDC as a category B biological weapon.
Web resources : Cryptosporidium parvum and cattle
Laboratory examinations : PCR.
Web resources : MED-VET-NET : The Giardia Cryptosporidium databases at The RIVM Epidemiological and Molecular typing Electronic Data InfraStructure
• Haemosporida [Haemosporina : a suborder of heteroxenous protozoa (subclass Coccidia, class Sporozoea) in which merogony takes place in a vertebrate, usually in the blood, and sporogony in the alimentary canal of a blood-sucking insect. Hemosporians are characterized by the independent development of macrogamete and microgamont; the absence of syzygy; the usual absence of a conoid; the production by the microgamont of eight flagellated microgametes; and the formation of a motile zygote (ookinete). Representative genera include
• Haemoproteus : a genus of coccidian protozoa in which the vectors are blood-sucking insects other than mosquitoes and the vertebrate hosts are mammals, reptiles, and wild and domestic birds including ducks, pigeons, and turkeys. In these organisms merogony takes place not in erythrocytes but in the vascular endothelial cells, and the gametocytes are found only in the circulating erythrocytes.
• Hepatocystis
• Leucocytozoon
• Plasmodium : parasitic in the erythrocytes of mammals, including humans, nonhuman primates, and rodents, birds, and reptiles, mainly lizards; it is transmitted to the bloodstream of mammals by the bite of female anopheline mosquitoes, in whose saliva the sporozoites are concentrated. From the bloodstream, the sporozoites migrate directly to the liver (exoerythrocytic stage), where they develop and multiply within the parenchymal cells as merozoites, which then burst the hepatocytes and invade erythrocytes. Erythrocytic schizogony then occurs and merozoites are free to invade other erythrocytes. Some merozoites develop into gametocytes, which are ingested by mosquitoes and begin the sexual stage, which ends with development of sporozoites. Avian malaria is transmitted by culicine mosquitoes; the vectors of reptilian malaria are unknown.
Epidemiology : globally all kinds of malaria / malarial, marsh, jungle or swamp fever / paludism cause:
• prevalence : 515 million people in 2002^ref. This is not far off double the estimate of 273 million cases produced by the WHO in 1998. And in areas outside Africa, the new figures are at least 3 times as high as those previously estimated by the WHO. During the 20th century, economic and social development and antimalarial campaigns have resulted in eradication of malaria from large swathes of the planet, reducing the world's malarious surface from 50% to 27%. In 2002 2.2 billion people were at risk from the mosquito-borne parasite : nonetheless, in view of expected population growth, by 2010, half the world's population--nearly 3.5 billion people--will be living in areas where malaria is transmitted^ref.
• Africa : 365 million cases in 2002
• Ethiopia : it is estimated that there are between 4 and 5 million malaria cases in each year. The geographical distribution depends mainly on altitude^ref. Outbreaks of malaria occur especially in the transition zones between highlands and lowlands, where climatic changes have profound effects on transmission^ref
• South Africa : there is excellent control of malaria. Nevertheless in 2 provinces, namely  Kwazalu Natal and Mpulamanga (formerly Transvaal), there is a risk of malaria  transmission, although it is very limited in the north and northeastern areas. In the past malaria was often introduced by people infected while travelling  through the Kruger Park, who then introduced the parasite while  seeking work into other areas where there were sometimes anopheline malaria vectors. The main vectors in South Africa are Anopheles gambiae,  which has spread malaria in the Kwazulu area; An. funestus, which has been the vector in the Drackensburg area; and possibly the related species An. aruni. Recently, in 1999-2000, An. funestus in the Kwazula area has shown resistance to the pyrethroid insecticides. Whether or not malaria cases in Gauteng were due to local  transmission or were imported remains questionable.
• Europe : the WHO Regional office estimates that  in the year 2000, nearly 20 000 malaria cases were reported. However, a survey in 2001 in Khatlon region showed that > 10% of the study population were asymptomatic parasite carriers of P. vivax and P. falciparum and indicates that the number of malaria cases may be as high as 150,000 to 250,000.
• Asia :
• south-east Asia and the Western Pacific : 25% of worldwide cases
• Kyrgyzstan : malaria was eradicated in 1959 but re-emerged in 1986 as a result of the importation of malaria by military personnel returning from Afghanistan. Anopheles algeriensis, An. claviger, An. hyrcanus s.l., An. martinius (formerly a synonym of An. sacharovi), An. messeae, and An. superpictus have been recorded in Kyrgyzstan. Malaria has been transmitted in the region by An. claviger, An. hyrcanus, An. messeae, and An. superpictus. In 1986 and 1987, 14 and 10 autochthonous malaria cases were detected, respectively. In 1988, 21 cases due to local transmission were registered. In 2001, the total number of cases reported was 15. In 2002, a total of 2267 autochthonous P. vivax cases were reported in the southwestern regions of the country, including Batken, Osh and Jalal-Abad^ref. The explosive resumption of malaria transmission in Kyrgyzstan was the result of immigration of a number of infected people from Tajikistan into the Batken region. In 2004-2005, there was a significant decrease in the reported number of autochthonous malaria cases (42 in 2005). However, in 2004 the first autochthonous case of P. falciparum malaria was reported in the Aravan district of the southern part of Kyrgyzstan, in an area bordering Uzbekistan, and in 2005 the number of autochthonous cases of P. vivax malaria increased in the outskirts of Bishkek, the capital of the country^ref. 88 cases of malaria from Kyrgyzstan in 2005 in contrast to the 42 the country reported theough WHO. This indicates that there may be some underreporting of cases. Disease rates in this country and neighboring Tajikistan have approached and even exceeded those of India and Thailand in recent years.
• China : 39,656 malaria cases in 2005, 45 of whom died. Up to 90% of malaria is found in the Yunnan province and Hainan island with an annual incidence in 2000 of below 10 per 1000 population^ref. Anhui province is regarded as a low risk area for malaria in China. We presume that all cases are Plasmodium vivax. It is a cause for concern that malaria is returning to an area previously regarded as very low risk. The CDC does not recommend malaria prophylaxis to visitors to Anhui Province^ref, and more information is needed before recommendations to travelers might be changed. A map of malaria in China for 2001^ref shows Anhui Province as having 0 to less than 1 case per 100,000 inhabitants.
• Nepal : in 2004, out of 27.3 million population of the country, 19.4 million are at malaria risk in Nepal. Out of that, 5.9 million reside in forests and forest fringes and inner Terai, 7.9 million in plain cultivated area and 5.6 million in hill areas. Malarious areas of the country have been stratified into 5 eco-epidemiological strata. From 1996 malaria cases have remained below 10 000 annually. Plasmodium falciparum proportion was 10 to 13 in 1996 and 1997 because of the outbreak in 1996 in Kanchanpur and in Nawalparasi  in 1997. Malaria incidence in the last 5 years has stabilized at around 8000 to 9000 cases annually. In 2000, there were 7616 cases with 7.4% of P. falciparum cases. Monthly distribution of malaria indicated that the disease is prevalent throughout the year with main concentration during the monsoon season. Even P. falciparum is found throughout the year. In the last fiscal year (1998-99) altogether 47,000 clinical malaria cases with 8900 (in 1999) confirmed malaria cases were recorded with morbidity rate due to malaria estimated at 0.35% for the area at malaria risk. The highest morbidity rate (API 7.3%) was in Kavrepalanchowk district where 29% of the total country confirmed malaria cases were recorded in 1999. For the VDC Mahadevsthan of the district where maximum cases were concentrated, the API was 45. During the period from 1995-1999, few severe malaria cases were recorded. There were 15 deaths in 1996 during the epidemic in Kanchanpur district.  The reported malaria cases keep on declining. However, it is important to notice that the probable malaria cases are going up continuously with 20 737 in 1998 to 63 933 in 2002.  During 2004, total 4637 laboratory confirmed cases were reported with 745 (16.1%) P. falciparum cases. However, the probable malaria cases during the same period were reported as 49,087^{ref1, ref2, ref3, ref4, ref5, ref6}.
• Myanmar (Burma) : in 2000 the overall country prevalence was 2.8 per 1000 population. 16% of the population in Myanmar lives in areas with high risk of malaria and, overall, the WHO estimates that 70% of the population live in areas with malaria transmission. Between 1991 and 2004, the proportion of Plasmodium falciparum malaria of all diagnosed malaria cases declined from 85% to 75%. In 2004, Myanmar reported 150,540 cases of malaria to WHO, of which 140,000 were P. falciparum^ref.
• Americas :
• Jamaica was certified free of malaria in 1966, but the vector, Anopheles albimanus, probably still exists on the island. Chloroquine resistance is for instance found in the southern parts of Panama, Columbia and the Amazon basin, whereas P. falciparum malaria in Haiti are susceptible to chloroquine. In 2006 there were 13 confirmed malaria cases^{ref1, ref2}. Jamaica confirmed 280 cases of malaria due to Plasmodium falciparum on the island between 6 Nov 2006 and 3 Feb 2007. Of these reported cases, 264 have occurred in Kingston, 12 in St. Catherine, 3 in St. Thomas, and one in Clarendon. There have been no reported deaths due to malaria^{ref1, ref2}. Official CDC recommendation posted on the CDC website is that the recommendation for malaria prophylaxis is limited to travelers staying overnite in the Kingston area
• Bahamas : an outbreak in 2006 consisted of cases by asymptomatic immigrants from a malaria-endemic country
• incidence = 300-500 millions new cases/yr
• USA : most of the 1200 cases of malaria diagnosed each year involve people who have traveled to infected areas; people can contract the disease also through tainted blood transfusions, intravenous needles, and unsanitary tattoo equipment. In the USA, 1320 cases of imported malaria were reported in 2004 (CDC. Locally acquired mosquito-transmitted malaria: a guide for investigations in the United States. MMWR 2006;55(No. RR-13):1--9), and 63 episodes of introduced malaria were detected from 1957 to 2003, the year when the latest episode occurred in Florida^{ref1, ref2}.
• Pakistan : both P. vivax and P. falciparum malaria are endemic in Pakistan in areas below 2000 meters elevation. The risk is usually much lower in cities, because the Anopheles mosquito needs clear water for breeding. the Sindh Province has historically had the highest incidence. Epidemics have occurred at 6- to 10-year intervals, the last one in 1972-73, and the present outbreak could be the start of a new epidemic. About 40% of cases are due to P. falciparum, which is significantly more common in the Sindh Province (64%). P.falciparum has developed resistance to chloroquine. The 2 main malaria vectors -- An. culicifacies and An. stephensi are both resistant to organochlorines and the latter has also developed resistance to malathion. There is also massive importation of malaria from Afghanistan. According to the recent Malaria Review Mission Report, 1998, malaria -- especially P. falciparum -- is on the increase in Pakistan. Slide-confirmed cases in the last 5 years have varied from a low of 73 516 in 1998 to a high of 111 836 in 1995. Pakistan's population is 139 million, and therefore the annual parasite incidence is less than one case per 1000. However, the actual level of malaria is at least 5 times higher than suggested by official records, since these are based on the 20% of clients who use government services. According to a conservative estimate, about 500 000 malaria cases occur per annum. Pakistan's malaria control programme is also facing organisational problems due to insufficient rapport between central headquarters and malaria control programmes in provinces, rapid turnover of staff, and relocation of recently trained specialists^ref
• Papua New Guinea : West Java is usually regarded as an area of low malaria endemicity. Papua Province is the part of island under Indonesian sovereignty (also known as Irian Jaya) and is known for high malaria endemicity and widespread resistance to chloroquine. Overall the reported number of malaria cases in Indonesia has been increasing: 161 285 cases in 1997 (50% P. falciparum) to 200 544 cases in 2001 (P. falciparum rate not available). Malaria remains a serious health problem in coastal and inland regions, affecting 15 provinces. It is endemic up to an altitude of 1200-1500 metres, where it becomes epidemic. Transmission is persistently high throughout the year, with Plasmodium falciparum causing an estimated 75% of infections. Malaria is the 3rd leading cause of hospital admissions and deaths. Among the contributing factors are shortages in health care personnel, breakdowns in drug supplies to rural areas, and lack of vector control. Only the higher mountainous areas and Port Moresby are malaria-free. Chloroquine resistance is regarded as widespread, and chloroquine should not be used for either treatment or prophylaxis. The overall risk of malaria in PNG was 1.7 per 1000 population in 2000 and 14.3 per 1000 in 2002 (WHO)
• mortality = 1-3.5 million deaths/yr (1 million deaths in sub-Saharan Africa alone, most of them children under 5 years old; some 3,000 Africans, mostly pregnant women and children, die from malaria each day). CFR = 15-30% for P.falciparum. Mortality has decreased from 3 per 100 000 in the 1970's to 0.9 per 100 000 in 1995,mostly in sub-Saharan Africa
• the economic costs for Africa alone are equivalent to US$12 billion annually^ref
• in the 1990s, between 10,000 and 12,000 cases of imported malaria cases were notified annually in the EU -- which is about 2-3 cases per 100,000 population^ref. In 2000, 15 528 cases of imported malaria were reported to the WHO Regional Office for Europe, with the largest numbers from France and the United Kingdom, which together accounted for about 65% of all cases (World Health Organization. Mosquito-borne diseases - Malaria. In: The vector-borne human infections of Europe. Their distribution and burden on public health (The Organization) pp. 13-24. Copenhagen: WHO Regional Office for Europe; 2004). Several factors influence the incidence of imported malaria, including endemicity in the areas visited, intensity of exposure, and compliance with and success of prophylactic measures. Data derived from Swedish travellers between 1997 and 2003 showed geographic differences in the crude risk of acquiring malaria ranging from 1 case per 100,000 travellers to Central America and the Caribbean and 5 per 100 000 in travellers to East and South East Asia, to 357 per 100,000 in central Africa^ref. Among those travellers, children below 6 years of age had a risk 4.8 times greater than adults. Of 1659 cases of falciparum malaria infection reported to the European Network on Imported Infectious Disease Surveillance (TropNetEurop) in 1999 and 2000, only a minority of patients reported having taken chemoprophylaxis appropriate to the resistance situation at their travel destination^ref. Within this group, west Africa contributed by far the greatest number of imported Plasmodium falciparum infections, with 68% (534/1659) of all cases in people migrating from the area and 59 percent (511/1659) of cases in shorter-term travellers. South East Asia in general, and Thailand in particular, have not been important contributors of imported malaria cases to the European region. Studies have identified a low incidence of falciparum malaria in travellers returning from Thailand^{ref1, ref2}. This risk is considered to be so low that for those visiting Bangkok and the main tourist areas of Thailand, the risk of potential serious side effects from malaria chemoprophylaxis far outweigh the risk of malaria infection, and, for example, chemoprophylaxis is advised for UK travellers only if they plan to visit areas of Thailand bordering Burma and Cambodia^ref. The TropNetEurop archives show an average of 1-4 cases of falciparum malaria reported annually since 1999, with an additional 1-3 patients annually with P. vivax malaria (unpublished data, TropNetEurop). An increase in the number of imported cases is not apparent. The current TropNetEurop surveillance map for imported malaria to Europe shows an increased signal from Laos caused by a single case. Thailand is not highlighted, but in 2005 2 cases were reported in Israel and in 2006 1 case in Germany. Most studies found that no matter which antimalarial is used for prophylaxis, 2-5% of travellers experience symptoms they perceive as serious side effects. This is the rationale for the current recommendations from most European countries against malaria prophylaxis for travel to countries in Southeast Asia like Thailand. The first problem with this approach is that some travellers will believe that because prophylaxis has not been recommended, there is no risk. This can only be addressed by better information. The second problem is that a local increase in risk -- like what we probably see here from Koh Phangan, Phuket Province -- is not noted by the Ministry of Health and is not reported, but is picked up by national and international surveillance systems like TropNetEurop. This situation would benefit from improved rapid reporting by the national authorities^ref. However, Ranong is the least populated Thai province, is mountainous, and in parts heavily forested, having the highest annual rainfall in Thailand. Given these factors, it is unsurprising that Ranong is malaria endemic^ref. Being a border area with Myanmar, mefloquine resistance is a concern and should not be used for prophylaxis against malaria in travelers to these regions. Doxycycline is an alternative to atovaquone-proguanil. Thailand exemplifies the potential hazards of prescribing anti-malarial prophylaxis simply by country. There is no risk in Bangkok and major tourist areas such as Koh Samui and Phuket, as reflected in the CDC and WHO guidelines, but hilly, forested regions near international borders are endemic. A travel specialist should therefore not recommend anti-malarial prophylaxis for all travelers to Thailand, but should assess whether the traveler will enter malarious areas of Thailand and advise accordingly.
Proteomics :
• the cysteine-rich interdomain region 1a (CIDR1a) of FCR3S1.2 (amino acids 395 to 700) of P. falciparum erythrocyte membrane protein 1 (PfEMP1) and phosphatidylserine on Plasmodium falciparum-infected erythrocytes binds to ...
• CD36 on DCs and modulate their function. CD36 mediates non-opsonic phagocytosis of infected erythrocytes^{ref1, ref2, ref3, ref4}. Sequestration of malaria-parasite-infected erythrocytes in the microvasculature of organs is thought to be a significant cause of pathology. Cerebral malaria (CM) is a major complication of Plasmodium falciparum infections, and PfEMP1-mediated sequestration of infected RBCs has been considered to be the major feature leading to CM-related pathology. Real-time in vivo imaging of sequestration using transgenic luciferase-expressing parasites of the rodent malaria parasite Plasmodium berghei revealed that: (i) as expected, lung tissue is a major site, but, unexpectedly, adipose tissue contributes significantly to sequestration, and (ii) the class II scavenger-receptor CD36 to which PfEMP1 can bind is also the major receptor for P. berghei sequestration, indicating a role for alternative parasite ligands, because orthologues of PfEMP1 are absent from rodent malaria parasites, and, importantly, (iii) cerebral complications still develop in the absence of CD36-mediated sequestration, dissociating parasite sequestration from CM-associated pathology^ref.
• Fab and Fc fragments on polyclonal B lymphocytes^{ref1, ref2} (but not differentiated IgG⁺ B lymphocytes), similar to the polyclonal B-cell activator Staphylococcus aureus protein A (SpA)^{ref1, ref2}, and induces proliferation, an increase in B-cell size, expression of activation molecules, and secretion of nonimmune IgM and cytokines (TNF-a and IL-6). Other IE moieties may also participate in this binding, as suggested by the partial competition (50%) mediated by recombinant CIDR1. Although the competition curve did not reach a plateau, the concentrations of recombinant CIDR1a used (up to 200 µg/ml) may exceed the molar concentration present at the surface of IE^ref. Crystallographic work has disclosed that the Ig binding domains in SpA are within areas of the polypeptide carrying a-helices and that the Fab- and Fc-binding sites are structurally separated^ref. It should be noted that the IgM binding domain of CIDR1a also harbors potential a-helical structures (amino acids 550 to 700) and similar contact residues as those present in protein A, yet the molecular details of the interaction remain to be explored. Taken together, these facts suggest that CIDR1a binds to B cells via the Fab fragments of Ig expressed at the B-cell surface, much as SpA does. Malaria-induced polyclonal B-cell activation has been reported in vivo^{ref1, ref2} and in in vitro studies involving the stimulation of total peripheral blood lymphocytes^{ref1, ref2}. The identification of P. falciparum-derived products and of the mechanisms responsible for B-cell activation has remained elusive though direct and indirect mechanisms mediated by T cells and accessory cells have been proposed to explain this phenomenon^{ref1, ref2, ref3, ref4}. CIDR1a directly activates in vitro purified B cells from nonimmune donors and binds to various Ig fragments and to Igs from different species and, therefore, could be defined as a superantigen. Since the proliferative response to CIDR1a was not high (a 2.5-fold increase compared to control antigen and media), the question arises whether this level of response would result in the polyclonal activation seen in vivo during malaria infections. It should be noted that in the present study the proliferation occurred in the absence of accessory cells and cytokines and was consistently observed in 26 of 26 experiments performed with lymphocytes from donors never exposed to malaria previously. In vivo the stimulatory capacity of CIDR1a may be enhanced by a multitude of cofactors: splenic B cells would be exposed to CIDR1a presented not only on the IE but phagocytosed and presented as soluble antigen or as immune complexes by follicular dendritic cells (FDCs) and dendritic cells (DCs) in the presence of cytokines, T helper cells, and costimulatory signals. Additionally, CIDR1a has been shown to induce CD4 T-cell responses in malaria immune and nonimmune donors^ref, a factor that in vivo could amplify by many times the magnitude of the response observed in the present study. It must be noted that in the present study purified T cells did not proliferate in response to CIDR1a, suggesting that the activation of CD4 T_h cells reported by Allsopp et al.^ref may involve cognate recognition on B cells or other antigen-presenting cells. The activation of B cells in vivo may occur in compartments with relatively high local concentrations of CIDR1a or as the result of direct binding to IE expressing CIDR1a, in which neighboring adhesive moieties of PfEMP1 may further enhance the IE-B-cell interaction. Moreover, blood-borne antigens (and thus malarial antigens related to the erythrocytic phase) are trapped mainly in the spleen, where B cells represent 50% of the splenocytes. The Ig binding properties of CIDR1a may serve to amplify its interaction with B cells, making it a key molecule, but potentially not the only one, involved in malaria-induced polyclonal B-cell activation. The fact that Ig-binding parasites (and therefore intravascular superantigens) are frequent in children in areas where malaria is endemic^ref may explain, at least in part, the prominent hypergammaglobulinemia and polyclonal B-cell activation that characterize human malaria^{ref1, ref2, ref3}. It has been suggested that during an infectious process IBPs of bacteria, viruses, and now CIDR1 of P. falciparum may divert specific Ab responses^ref. P. falciparum, one of the most successful human pathogens, has evolved multiple evasion mechanisms including clonal antigenic variation and diversity^{ref1, ref2}, T-cell antagonism^ref, and hindrance of dendritic cell maturation^ref. It is tempting to speculate that the polyclonal B-cell activation described here is another virulence mechanism that contributes to the evasion of efficient host responses. The results may suggest that the large var gene family encoding PfEMP1 has evolved not only to mediate the sequestration of IE but also in order to manipulate the immune system and to allow for the survival of the parasite.
• PECAM-1/CD31^{ref1, ref2}
P.falciparum skeleton binding protein 1 (PfSBP1)functions at the parasitophorous vacuole membrane to load PfEMP1 into Maurer's clefts during formation of these structures at the P.falciparum-infected erythrocyte surface^ref
• purified GPI induces ... :
• macrophage activation and secretion of TNF. Myd88 (TLR adaptor protein)-deficient mice fail to produce IL-12 during infection with Plasmodium berghei^{ref1, ref2, ref3}
• NK1.1^-, CD1d-restricted T cells proliferation and production of IL-4 upon binding to Va14/Vb8 TcR^ref
• a GPI-linked toxin decreases TNF-a and IL-10 secretion : NO^. creates nitroTyr residues that activate iNOS.
• purified Plasmodium falciparum schizont lysate activates TLR9^ref on :
• gd-T lymphocytes, inducing upregulation of CD69 expression and IFN-g production. Schizont-associated antigen (SAA)^ref, monophosphate and diphosphate esters, MALag1 and MALag2^ref could bind to gd-TcR
• PDCs, inducing in human cells IFN-a production, but a weak inducer of cell maturation (induces CD86, but not CD40, expression). Conversely, our findings also suggest that in murine cells, the same schizont-soluble fraction is a weak stimulator of IFN-a production, but a strong inducer of cell maturation (induces both CD86 and CD40 expression). Other products from the parasite, such as glycosylphosphatidylinositol and malaria pigment, are also known to activate human monocytes to produce cytokines^{ref1, ref2}. The possible role of PDCs in human malaria is further supported by the findings of a significant reduction of circulating PDCs in patients. One possible mechanism for the loss of PDCs in the blood is due to the mobilization of cells to secondary lymphoid tissues such as the spleen, where marked immunological activity has been observed^ref. The migration capability of PDCs requires chemokine stimulation and induction of CCR7^ref. Schizont-stimulated PDCs up-regulate the expression of CCR7, providing a potential explanation for the decrease in blood PDCs seen in malaria infection. A possible scenario for P. falciparum-mediated PDC activation in vivo may start with the rupture of blood stage schizonts, releasing soluble molecules that activate PDCs via the TLR9-MyD88 signaling pathway. The stimulated PDCs produce IFN-a and enhance the response of  T cells that have been simultaneously primed with a schizont-derived phosphorylated molecule. Further characterization of the complex nature of parasite ligands that activate PDCs will provide new insight into innate immunity and its role in the pathogenesis of malaria infection.
Although the only known ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA.
• PxSR (scavenger receptor homologue) might prevent activation of innate mechanisms in mosquitoes by competition with mosquito scavenger receptors^ref.
• heme synthesis :


Transmission :


(reproduced with permission from Nature Reviews Immunology (Vol 4, No. 3, pp 169-180 (2004)) copyright Macmillan Magazines Ltd)
mosquito ingests microgametocytes and macrogametocytes during blood meal : they become microgametes and macrogametes and fuse each other in the mosquito midgut to create motile diploid zygotes => ookinetes, that attach to the epithelial cell surface at the apical tip, rupture the cell membrane via membrane-attack ookinete protein (MAOP) (a microneme protein with a membrane-attack complex and perforin (MACPF)-related domain^ref) and migrate through the cytoplasm toward the basal lamina, on which they undergo meiosis and subsequent mitosis to create oocyst, whose rupture ....

.... liberates many sporozoites which infect salivary glands of the vector via thrombospondin-related anonymous protein (TRAP) (sporogonic cycle : ~ 10-40 days; impossible over 2,000-2,500 m altitude) ==transmission of sporozoites by females of Anopheles spp.==> traversing the liver sinusoidal cell boundary and wounding of hepatocytes by sporozoite migration via another previously identified MACPF-related molecule induces the secretion of HGF. This then interacts with its receptor MET, triggering a pathway leading to the rearrangement of the actin cytoskeleton of neighboring hepatocytes, rendering them susceptible to infection (it may explain why severe malaria cases are more frequent in HBV carriers, who have elevated HGF levels, than in matched controls) => once sporozoites have invaded hepatocytes (exo-erythrocytary cycle or incubation) via TRAP, they can undergo latency (hypnozoites) or intracellular schizogony (every schizont (cryptozoite) create many metacryptozoites that then develop into merozoites). Cycle occurs only if 16 < T < 33 °C. Merozoites inhibit DC maturation, enhance IL-10 production and decrease IL-12 production, indirectly inhibiting IFN-g release from CTL. Merozoites infect 2÷7 % of RBCs (erythrocytary cycle) via the glycophorin A erythrocyte–merozoite invasion pathway (in a sialic acid-dependent manner in Plasmodium falciparum strain W2mef and in a sialic acid-independent manner in strain 3D7; including the transmembrane erythrocyte-binding protein 175 (EBA-175); invasion requires shedding of ectodomain components of 2 essential surface proteins, called MSP1 and AMA1, by PfSUB2, an integral membrane subtilisin-like protease (subtilase) stored in apical secretory organelles called micronemes. Upon merozoite release it is secreted onto the parasite surface and translocates to its posterior pole in an actin-dependent manner, a trafficking pattern predicted of the sheddase. Subtilase propeptides are usually selective inhibitors of their cognate protease, and the PfSUB2 propeptide is no exception; recombinant PfSUB2 propeptide binds specifically to mature parasite-derived PfSUB2 and is a potent, selective inhibitor of MSP1 and AMA1 shedding, directly establishing PfSUB2 as the sheddase. PfSUB2 is a new potential target for drugs designed to prevent erythrocyte invasion by the malaria parasite^ref) and become immature trophozoites (ring stage) (neither micronemes nor rhoptriae; it uses hemoglobin through micropore and oxidize heme inducing its polymerization to hemozoin => hemolysis => melanosis; induction of protein that cause RBC adhesion to endothelial ICAM-1) : then they can undergo either evolution to mature trophozoites and subsequent schizogony cycles or meiosis to create microgametocyte and macrogametocyte, that cannot fuse when in bloodstream of Homo, but only in the vector gut. Signaling via the erythrocyte b₂-AR and Ga_s regulates erythrocytic stages of malarial infection across Plasmodium species : because they are internalized and associated with the vacuolar parasite, their activation in malarial infection may regulate a step of vacuole formation that is conserved across parasite species. Activation of T_reg lymphocytes contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses : depletion of CD4⁺CD25⁺ regulatory T lymphocytes (T_reg) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and this protection is associated with an increased T-cell responsiveness against parasite-derived antigens^ref. As the malaria parasite, Plasmodium falciparum, grows within its host erythrocyte it induces an increase in the permeability of the erythrocyte membrane to a range of low-molecular-mass solutes, including Na⁺ and K⁺. This results in a progressive increase in the concentration of Na⁺ in the erythrocyte cytosol. The parasite cytosol has a relatively low Na⁺ concentration and there is therefore a large inward Na⁺ gradient across the parasite plasma membrane. The parasite exploits the Na⁺ electrochemical gradient to energize the uptake of inorganic phosphate (P_i), an essential nutrient. Pi was taken up into the intracellular parasite by a Na⁺-dependent transporter, with a stoichiometry of 2Na⁺:1P_i and with an apparent preference for the monovalent over the divalent form of P_i. A Pi transporter (PfPiT) belonging to the P_iT family was cloned from the parasite and localized to the parasite surface. Expression of PfPiT in Xenopus oocytes resulted in Na⁺-dependent P_i uptake with characteristics similar to those observed for P_i uptake in the parasite^ref. The intraerythrocytic malaria parasite derives much of its requirement for amino acids from the digestion of the haemoglobin of its host cell. However one amino acid, isoleucine, is absent from adult human hemoglobin and must therefore be obtained from the extracellular medium. In this study we have characterised the mechanisms involved in the uptake of isoleucine by the intraerythrocytic parasite. Under physiological conditions the rate of transport of isoleucine into human erythrocytes infected with mature 'trophozoite-stage' P. falciparum parasites is increased to approximately 5-fold that in uninfected cells, with the increased flux being via the 'new permeability pathways' (NPP) induced by the parasite in the host cell membrane. Transport via the NPP ensures that protein synthesis is not rate-limited by the flux of isoleucine across the erythrocyte membrane. On entering the infected erythrocyte, isoleucine is taken up into the parasite via a saturable, ATP^-, Na⁺-, and H⁺-independent system which has the capacity to mediate the influx of isoleucine in exchange for leucine (liberated from hemoglobin). The accumulation of radiolabelled isoleucine within the parasite is mediated by a second (high-affinity, ATP-dependent) mechanism, perhaps involving metabolism and/or the concentration of isoleucine within an intracellular organelle^ref.
Malaria remains one of the most important causes of human mortality^ref. This epidemiological success of the parasite is at least partly due to its very high intensity of transmission, leading, on average, to several hundred infections per year in humans living in areas with the most intense transmission^ref. It became clear with the earliest models of the epidemiology of malaria that this intense transmission is largely due to the part of the parasite's life-cycle that takes place within the mosquito vector [Macdonald G (1957) The epidemiology and control of malaria. London: Oxford University Press], and in particular to the interaction between the life-span of the mosquito, the duration of the parasite's development, and the mosquito's biting rate. More recently, ideas have moved from the epidemiological description of these interactions to the evolutionary idea that the parasite might manipulate the mosquito's behaviour to enhance its transmission. Thus, malaria parasites manipulate various aspects of their mosquito vector's biting behaviour in ways that should increase their transmission success^ref. When the parasites have completed their development within the mosquito and have thus developed into the sporozoite stage, which can be transmitted by a bite on a human host, they increase the biting frequency, and thus the rate of contact between mosquitoes and humans and, consequently, the rate of transmission^ref. In contrast, at an earlier developmental stage (i.e., as oocysts, the non-transmissible developmental stage of the parasite), they decrease the biting rate by decreasing the mosquito's motivation to bite^{ref1, ref2}. Thus, as biting is risky, the probability that the mosquito survives the parasite's development to the transmissible sporozoite stage is increased during early pre-sporozoite development. During their development within the human, malaria parasites should be expected to manipulate the mosquito's biting behaviour by making infectious humans (i.e., those harbouring gametocytes) more attractive to mosquitoes. This would not only increase the parasite's transmission, but would also have a strong effect on the epidemiology of malaria^ref. However, while increased feeding on infected hosts has been observed in some studies^{ref1, ref2}, others do not show increased attractiveness^ref; the question of behavioural manipulation by gametocytes to increase the host's attractiveness to mosquitoes therefore remains a controversial issue in the biology of malaria. One of the reasons for the lack of conclusive studies is that individual people vary considerably in their intrinsic attractiveness to mosquitoes^{ref1, ref2}. Attractiveness depends on, for example, human sweat components^ref, body temperature and moisture^{ref1, ref2}, or body odour and breath^ref (human breath, although known to contain semiochemicals that elicit behavioural and/or electrophysiological responses (CO₂, ammonia, fatty acids) in An. gambiae also contains one or more constituents with allomonal (~repellent) properties, which inhibit attraction and may serve as an important contributor to between-person differences in the relative attractiveness of humans to this important malaria vector^ref). This background variation makes it difficult to find an effect of manipulation and, more importantly, to be certain that any observed difference is due to infection rather than to a difference in intrinsic attractiveness. Indeed, without a proper control, any observation of increased attractiveness by people infected with gametocytes might mean that harbouring gametocytes is a consequence of being very attractive to mosquitoes (and thus being infected frequently) rather than vice versa. However, the variability of intrinsic attractiveness to mosquitoes could be accounted for with a comparison of 2 measures of the attractiveness of individuals: the first when they are infected and the second when they have cleared the parasite. A 2005 study estimated, in semi-natural conditions, the extent to which malaria gametocytes enhance the attractiveness of asymptomatic humans to mosquitoes in the area around Mbita, Nyanza Province, Kenya between April and July 2004 (with the agreement of the Kenya National Ethical Review Committee). 12 groups of 3 children were considered who were between 3 and 15 y old : this age-class constitutes the main reservoir of gametocytes in the area of Mbita^ref. After informed consent was obtained by the parents or guardians, apparently healthy children from local primary schools were screened for malaria in the morning. Each day, 3 children were chosen to participate in the study: one who was uninfected, one infected with the asexual (non-infective) stage of the malaria parasite Plasmodium falciparum, and one harbouring the parasite's gametocytes (the stage infective to mosquitoes). Note that symptomatic children (i.e., with increased temperature or other symptoms of disease) were immediately referred to the health clinic for proper treatment and therefore did not participate in the study. The attractiveness of the children in each group was measured with a 3-way olfactometer consisting of a central chamber attached with PVC tubes to 3 tents where the 3 children of the group were resting or sleeping^ref. Mosquitoes were released in the central chamber and given the opportunity to follow their preferred odour. To account for the variability of intrinsic attractiveness to mosquitoes, we treated all children with detectable parasitaemia with Fansidar and assayed the same children 2 wk after their first assay. Although it is not clear whether Fansidar kills gametocytes, subsequent microscopic examinations confirmed, in each of the 12 groups, that the children had cleared the parasite before the second assay. Thus, the first assay showed the combined effects of intrinsic and parasite-induced attractiveness, while the second assay gave an indication of the intrinsic variation of attractiveness among the children; the difference between the 2 assays could be used to analyse the effect of infection above the background variation. The total number of mosquitoes attracted to the set of children in a group was similar before (20.6 mosquitoes per triplet) and after (18.6 per triplet) treatment with Fansidar. Before treatment, mosquitoes preferred the gametocyte carriers, so that, on average, 10.2 mosquitoes were attracted by the gametocyte carriers, 5.3 by uninfected children, and 5.4 by children harbouring asexual stages. That the strong attraction of the gametocyte carriers was indeed due to the presence of the gametocytes is suggested by the fact that, after treatment, the children who had previously harboured gametocytes attracted a similar number of mosquitoes (4.4) to both the children who had previously harboured asexual stages (5.8) and the previously uninfected children (8.1). This pattern was confirmed with a statistical analysis that considered the difference between the proportions of the mosquitoes (relative to the 100 or so that were added to the olfactometer) attracted to gametocyte carriers before and after treatment. Indeed, after treatment, mosquitoes were approximately 14% less likely to be attracted to the former gametocyte carriers than before treatment. As a considerable number of mosquitoes did not respond to the odours of the 3 children (which is often the case when mosquitoes are used in experimental set-ups), researchers also considered only the mosquitoes that responded to the children's odours and compared the proportion of the mosquitoes within a replicate attracted to the gametocyte carrier before treatment and after treatment. In most replicates, the gametocyte carrier attracted more than a third of the mosquitoes before he or she had been treated, but attracted a smaller proportion of the mosquitoes after treatment. This result suggests, again, that the gametocytes enhance the attractiveness of their host. This visual analysis was confirmed by a statistical one, which showed that the difference between the proportion of mosquitoes attracted to the gametocyte carrier before and after the treatment is > 0. A Wilcoxon signed-rank test gave a similar result with p = 0.052. (Note that the statistically significant finding, despite a small number of groups, emphasises the role of the gametocytes in determining attractiveness to mosquitoes above the intrinsic variation of attractiveness among individuals). The analysis shows that increased attractiveness was not due to an intrinsic attractiveness of gametocyte carriers but to the infection status associated with the presence of gametocytes. The mechanism underlying this manipulation is unknown, but it is likely that the parasites change the infected individual's breath or body odour, as these are involved in attracting mosquitoes at the distances involved in our experiment^{ref1, ref2}. While transpiration and body temperature also attract mosquitoes at these distances^ref, these factors are less likely to be involved in the manipulation as the infection was asymptomatic in all of the children involved in the study. A striking aspect of the results is that former gametocyte carriers (i.e., after treatment) seem to repel mosquitoes, as only 22%, i.e., less than one third, of the responding mosquitoes prefer these children. An explanation for this result could be based on the slight anaemia in previously infected children. Mosquitoes might sense this anaemia and prefer those children with a higher concentration of red blood cells as it is these that the mosquitoes require. This would indicate a remarkable adaptation by the mosquitoes. The interpretation, however, would predict that the children previously infected with the asexual stage should also repel mosquitoes—but this was not observed. Indeed, as 47% of the mosquitoes preferred these children, there was a tendency for the opposite effect. In conclusion, the data suggest that mosquitoes are more attracted to humans infected by the transmissible gametocyte stage of malaria parasites than to uninfected individuals or individuals infected with asexual, non-transmissible stages. Previous studies have shown that malaria also manipulates the mosquito's biting behaviour at the oocyst stage (when infection decreases the motivation to bite and thereby increases the probability that the mosquito survives the parasite's development)^{ref1, ref2} and at the sporozoite stage (when infection increases both the motivation to bite and the biting frequency)^{ref1, ref2}. Thus this study completes the picture by demonstrating that the gametocyte, the only transmission stage from the human to the mosquito, manipulates the biting behaviour of its vector to enhance its transmission to the vector. Apart from the diversity of mechanisms employed by the parasite to manipulate its vector and increase its transmission, what is striking about the set of demonstrations of behavioural manipulation is that the parasite appears to influence the parameters that are most critical for transmission and thus for the parasite's fitness [Macdonald G (1957) The epidemiology and control of malaria. London: Oxford University Press]: the biting rate of the mosquitoes when they become infected and when they infect humans and, consequently, the mosquito's mortality during the parasite's development. Such manipulation therefore has a profound effect on the epidemiology of disease and, if it is not considered, can lead to severe biases in our estimates of the intensity of malaria transmission^ref.
Few studies have investigated susceptibility to severe placental malaria infection (apart from in primigravida^ref). Reduced fetal growth^ref and maternal anaemia sequelae^ref are known, however, to have serious consequences. Maternal shortness ("stunting"), and small skeletal size and thinness ("wasting") are associated with a greater likelihood and severity of placental malaria; the dose-response relationship indicates a causative biological mechanism^ref
Presumed mechanisms of adaptive immunity to malaria stage by stage :
• antibodies block invasion of sporozoites into liver cells
• IFN-g and CD8⁺ T cells inhibit parasite development in hepatocytes
• antibodies block invasion of merozoites into erythrocytes
• antibodies prevent sequestration of infected erythrocytes by preventing binding to adhesion molecules on the vascular endothelium
• IFN-g and CD4⁺ T cells activate macrophages to phagocytose intra-erythrocytic parasites and free merozoites
• direct contact between NK cell and infected erythrocyte is required for full NK-cell activation^ref. NK cells are cytotoxic for infected erythrocytes^ref
• reduced levels of serum MBL are associated with increased risk of severe Plasmodium falciparum malaria^ref. MBL-A deficiency does not affect hepatic invasion by Plasmodium yoelii sporozoites^ref. MBL binds glycoproteins on infected erythrocytes, but does not affect parasite growth^ref
• antibodies neutralize parasite glycosylphosphatidylinositol and inhibit induction of the inflammatory cytokine cascade^ref
• antibodies mediate complement-dependent lysis of extracellular gametes, and prevent fertilization of gametes and the development of zygotes
• a marked increase in circulating gd T cells has been reported in malaria patients^{ref1, ref2}. The increased  T cell response in malaria could have both beneficial and deleterious effects. gd T cells have been shown to directly inhibit the growth of blood stage parasites in vitro^ref. However, a marked increase in gd T cell activity associated with high levels of proinflammatory cytokines can cause pathology^ref. In the mouse model the accumulation of  T cells in the brain is found to be associated with cerebral malaria^ref.
Immune evasion : malaria parasites are almost entirely confined to the bloodstream, suggesting that the blood stage parasites and their products continue to interact with host immune cells. Parasite products released from rupturing schizonts have been shown to activate cellular components of the innate immune system to produce proinflammatory cytokines^ref.
• the parasites have a 4-stage life cycle with a stage-specific expression of many proteins at each stage : these proteins tend to be highly polymorphic, and thus they are able to evade Ag-specific immunity. Cytoadhesion of infected red blood cells (iRBC) is mediated through parasite-encoded, clonally variant surface antigens (VSA) and is a central process in the pathogenesis of Plasmodium falciparum malaria. Mutually exclusive transcription of var genes is linked to the dynamic remodeling of chromatin by a protein homologous to yeast Sir2 called PfSir2, which forms a chromosomal gradient of heterochromatin structure and histone hypoacetylation^{ref1, ref2}.
• the majority of the malaria parasite’s life cycle occurs within the RBC, thus excluding them both from the Ab attack and from killing by CTLs, as mature RBC do not express HLA molecules
• late blood stage parasites adhere to the endothelium of blood vessels, helping them to evade splenic clearance
• the binding of blood stage parasites to myeloid dendritic cells (DCs)^ref inhibits cell maturation, leading to a suppression of the T cell response^ref.
Species :
• Plasmodium cynomolgi
• Plasmodium falciparum

Epidemiology : Snow and colleagues claim that their estimate of 515 million cases of malaria caused by Plasmodium falciparum globally is up to 50% higher than that reported by the WHO, and 200% higher for areas outside Africa. However, this comparison refers to the WHO's estimates from 1990 and 1998, and not to the range of 300 million to 500 million that the WHO has used since 2000. Both groups agree that the burden of malaria disease outside Africa, especially in South Asia, is greater than was estimated in the 1990s^ref. However, the design of their model and its inputs have led to a significant overestimate of the malaria burden outside Africa — as in the example of the WHO western Pacific region (WPR), for which their model predicts 60 times the 2002 incidence reported by national malaria-control programmes^{ref1, ref2}. Severe forms still have high rates of death and disability in sub-Saharan West Africa (1 million new infections every day in 2002), and cause 1.5 to 2.7 million deaths each year; inoculation rates approaching 0.5 infected bites per night is not unusual
• India : Rajastan is endemic for malaria, and in the period from 1986 to 1997, the annual parasite rate in Rajastan was 5 to 10 cases per 1000 population, of which 10-25% were P. falciparum and the remaining were P. vivax
• Thailand is not malaria-free and 2 studies have found an monthly incidence of P. falciparum malaria of about 1 per 35,000 travelers and 1 per 15,000 travelers of all species of malaria^{ref1, ref2}. This risk is considered so low that the risk of serious side effects from malaria chemoprophylaxis far outweigh the risk of malaria infection. 3 cases reported in returning tourists in May 2006 may indicate an increasing risk in southern Thailand, and a comment from the Thai authorities would be welcome. Thailand reported 37 335 malaria cases in 2004 with 325 fatalities and a P. falciparum rate of 51%^ref. The report also state "In southern peninsula, there has been re-emergence of malaria transmission in many districts where it has been eradicated. Phuket province reported indigenous cases where it has been eradicated earlier. One of the main reasons for this problem is illegal migrant labour force from Myanmar. A recent update on malaria in the Thai population of southern Thailand is needed, but at present it would probably be premature to introduce a recommendation of chemoprophylaxis to all travellers to southern Thailand
• In the Caribbean region, malaria has been eliminated from all islands except Hispaniola, the island consisting of Haiti and the Dominican Republic. P. falciparum causes 99% of malaria cases in Haiti and the Dominican Republic (MD Milord, Ministry of Public Health and Population, Haiti, and JM Puello, National Center for Control of Tropical Diseases, Dominican Republic, personal communication, 2006), which share the only Caribbean island still endemic for malaria. Conversely, P. vivax causes 94% of cases in Mexico and Central America^ref
• Dominican Republic : 21 cases of malaria in travelers to resort areas. Plasmodium falciparum malaria has been confirmed in 5 patients from the USA, 6 from Canada, and 10 from European countries (5 in Germany, 1 in Spain and 1 in UK), all of whom had recently traveled to La Altagracia (including Punta Cana) and Duarte provinces (San Francisco de Macoris) , areas of the Dominican Republic where malaria had not previously been reported. All returned home between 3 Nov 2004 and 10 Jan 2005. In rural areas of the Dominican Republic, P. falciparum malaria is endemic, with the highest risk in the far western region of the country, and prophylactic medication with chloroquine is recommended for incoming travelers. Conversely, urban and resort areas in the Dominican Republic have been considered nonmalarious, and prophylactic medication has not been recommended for persons traveling to these areas (CDC. The yellow book: health information for international travel, 2003-2004. Atlanta, GA: US Department of Health and Human Services, CDC; 2003) in Duarte Province. 16 returned home during 3-16 Nov 2004, and one returned 20 Dec 2004; all were admitted to hospitals, and 6 required treatment in ICUs. On 24 Nov 2004, CDC expanded its recommendations for chloroquine prophylaxis for travelers to the Dominican Republic to include all of La Altagracia and Duarte provinces, in addition to rural areas countrywide^ref. However, CDC has rescinded recommendations for malaria prophylaxis for Duarte Province because no new cases have been reported from the area in the last 2 months, the epidemiologic investigation by the Ministry of Health of the Dominican Republic did not reveal any new cases, and their surveillance system did not detect any cases of malaria in the province in recent years^ref. The revised recommendations advise clinicians and travelers about the expanded malaria risk area, so that any febrile persons who have visited these areas will receive prompt diagnosis and treatment to avoid severe complications. Major networks of blood collection agencies and the Food and Drug Administration also were contacted. Similar alerts were issued by health officials in Europe and by the Public Health Agency of Canada. The MoH investigation included active case detection and entomologic investigations in La Altagracia and Duarte provinces. In Duarte Province, officials confirmed that no other cases had been reported during 2003-2004. Nonetheless, MoH is taking precautionary measures, including enhanced surveillance. In La Altagracia Province, MoH surveillance data have identified an increase in cases of malaria beginning in November 2004 among migrant workers in the Bavaro Zone, 10 miles from the Punta Cana resort area. MoH intensified control measures in the Bavaro Zone, which include 1) presumptive treatment of all construction and hotel workers by using directly observed therapy with chloroquine and primaquine, and 2) mosquito control through residual and spatial insecticide spraying and application of larvicide to suspected breeding sites. Measures instituted in the Punta Cana resort area include intensified surveillance and larvicide application. This report describes an outbreak of malaria in areas in the Dominican. Republic previously thought to be nonmalarious. P. falciparum is the only malaria parasite in the Dominican Republic and has remained susceptible to chloroquine. Because P. falciparum malaria can be rapidly fatal, travelers should be aware of risk areas so that they can take appropriate preventive measures; clinicians should consider malaria in their diagnosis and treatment of febrile illness in travelers. Malaria can be prevented by taking an antimalarial drug and by preventing mosquito bites. Chloroquine is the recommended drug for malaria prevention for persons traveling to the Dominican Republic and is highly efficacious and well tolerated by most travelers. To prevent mosquito bites, travelers should use insect repellent containing up to 5% DEET and wear long-sleeved clothing; if not staying in screened or air-conditioned housing, they should sleep under a net, preferably one treated with insecticide. Rapid intervention is crucial for ill travelers with suspected malaria^ref. In nearly all cases in this outbreak, delays in diagnosis and treatment occurred; in certain cases, delays contributed to serious illness. During July 1999--March 2000, a previous outbreak in the Dominican Republic occurred among European travelers to Punta Cana, principally in the Bavaro Zone. Factors identified as contributing to that outbreak were 1) the increased breeding of A. albimanus mosquitoes, the predominant malaria vector in the Dominican Republic, in the wake of Hurricanes Mitch and George and 2) malaria-infected migrant workers. In 1999, approximately 3000 malaria cases were reported in the Dominican Republic, a 50% increase over the number of cases in 1998^ref. During the 1999-2000 outbreak, CDC travel recommendations were temporarily expanded to recommend chloroquine prophylaxis for all areas in La Altagracia Province; this recommendation was rescinded 2 months later after MoH increased surveillance and controlled the outbreak. In September 2004, Hurricane Jeanne struck the Dominican Republic. The east coast, including Punta Cana and the Bavaro Zone, received heavy rains and flooding, which might have resulted in increased breeding of mosquitoes. In addition, construction in Punta Cana and the Bavaro Zone has brought in many migrant workers from areas where malaria is endemic. The ongoing MoH investigation will attempt to determine whether these factors have contributed to the recent increased transmission. MoH surveillance data indicate that, on average, approximately 1500-2500 malaria cases are reported annually in the Dominican Republic; in 2004, a total of 2012 cases had been reported through November. Effective surveillance systems and rapid communication among surveillance networks are crucial to detecting cases of malaria and intervening in areas that are usually nonmalarious. During this outbreak, rapid communication among surveillance networks in North America, Europe, and the Caribbean led to prompt diagnoses and timely public health interventions to prevent additional cases among residents of and travelers to the Dominican Republic^ref. The question whether the cases come from the 2 provinces where tourists concentrate, and what the risk is in the rest of the island, remain unanswered. Numbers of malaria cases in the local population would be important. Antimalarial drugs taken correctly and consistently, along with other measures to prevent mosquito bites, have been shown to be effective in preventing malaria. Therefore, CDC does not discourage travel to malaria-endemic countries. On 15 May 2005 the CDC lifted the outbreak notice for travel to La Altagracia Province, Dominican Republic, including the resorts at Punta Cana. No new malaria cases in travelers have been reported from the area since January 2005; the numbers of malaria cases in the Dominican Republic have returned to what is normal for this province. The outbreak notice for Duarte Province was lifted on 23 Feb 2005. 20 cases of malaria were reported in people who had traveled to resort areas in La Altagracia Province from 3 Nov 2004 to 10 Jan 2005, and a single case in a traveler to Duarte Province who returned in early November 2004. 5 of the travelers were from the US, 6 from Canada, and 10 from Europe (These resort areas had previously been malaria-free)^ref.
• Bahamas : 19 confirmed malaria cases in May-June 2006 in Great Exuma, an area where malaria transmission does not normally occur and for which antimalarial drugs have not previously been recommended. 13 cases occurred in residents of the Bahamas, and an additional malaria infection was confirmed in a U.S. citizen who traveled to Great Exuma in early May 2006^ref. All these confirmed infections were caused by Plasmodium falciparum. Most of the patients reported no recent travel to malaria-endemic areas, but some of the Bahamas residents may have recently traveled from Haiti, where P. falciparum is endemic. At this time, CDC is recommending chloroquine as an antimalarial medication for travelers to Great Exuma. This recommendation is expected to be temporary and does not apply to other islands of the Bahamas. The Bahamas are considered to have been free of malaria in historic times along with the Azores, Bermuda and St Pierre Miquelon islands. The theory that the present chain of transmission starts with P.falciparum-infected immigrants from Haiti seems plausible, and the infections demonstrate that Anopheles mosquitoes, capable of transmitting malaria are found on the Bahamas. If 16 people have been infected, it seems to indicate that one than just one gametocyte carrier is involved. If so, in addition to aerial spraying to control the outbreak, a systematic survey of blood films from immigrants from P. falciparum-endemic areas who have arrived within the past 3 weeks to the Bahamas, and treatment of such patients, may help to stop the outbreak^{ref1, ref2}
Genomics : about 5,300 genes, just 34% encode proteins with known functions.  88% of predicted genes are expressed in at least one stage of the lifecycle and show the shift in transcription from protein synthesis through to cell surface structures. 43% of genes are cell-cycle regulated, while 51% are constitutively expressed, including housekeeping and hypothetical genes with no human equivalent orthologue, which could represent targets for drug development
Resistance :
• serum factors : mannose-binding lectin (MBL) deficiency => low serum MBL levels assocaited with increased risk of severe malaria^ref
• iNOS / NOS2 : NOS2A-1659T is associated with increased susceptibility to cerebral malaria; NOS2A-954C and NOS2A-1173 are associated with protection from clinical malaria and severe anaemia, respectively^{ref1, ref2, ref3}
• cell-surface molecules :
• HLA-B*5301 (=> liver stage anti-malarial vaccines because hepatocytes, but not RBCs, display class I molecules !), HLA-DRB1*, and HLA-DRB1*0101, and HLA-DRB1*1352 gene^ref
• deletion in glycophorin C
• absence of Tn and En(a) erythrocytary antigens
• IFNGR1 -56 heterozygous individuals are protected from cerebral malaria^ref
• IFNAR1 : 17470-G/G and L168V-G/G genotypes are associated with protection from cerebral malaria^ref
• CD36 / scavenger receptor : -14C=>T and -53G=>T promoter polymorphism are associated with protection from cerebral malaria^ref; mutations leading to reduced expression are associated with increased risk of severe malaria^ref; nonsense mutation are associated with protection from severe malaria^ref
• KIR3DL2 : association with malaria-specific IFN-g production by NK cells^ref
• CD40L 726C : X-linked; marked reduction in risk for severe malaria in hemizygous males^ref
• cytokines :
• TNF2 : promoter polymorphism that affects OCT1 binding increases susceptibility to cerebral malaria^{ref1, ref2}
• IL4 -524T : increased malaria-specific antibody levels^ref
• IL12B : promoter polymorphism leading to decreased IL-12 production associated with increased mortality in Tanzanian but not Kenyan children^ref
• thalassemias and hemolytic anemias (pyruvate kinase deficiency in mice protects against malaria)
• many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. A peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease detects IFN--secreting CD4⁺ T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many HLA-DR types. The correlation is observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells^ref
Symptoms & signs : malignant tertian fever / tropical tertian fever / malaria tertiana / summer-autumn or falciparum malaria : 6-19 dd. incubation => fever with chills, headache, myalgia, hepatomegaly (bronze liver), hyperreactive malarial splenomegaly / tropical splenomegaly syndrome, nausea and vomiting, abdominal pain, diarrhea, Maurer spots in 3-20% RBCs => hemolytic anemia. Schizogony occurs every 48 hrs, together with fever (crisis defervescence). Self-limiting within 3 weeks or complicating by a kinin that causes increase in blood-brain barrier permeability => reversible increase in endocranic pressure and cerebral oedema due to obstruction of blood flow and a systemic or local increase of proinflammatory cytokines  => sequestration of infected RBCs in the brain capillaries (pernicious or cerebral malaria (CM) in individuals with TNF-a-308 polymorphism and hypoargininaemia) => ARDS, algidism, coma. Severe malaria is also associated with retinopathy, which have been found in 77% of patients with CM : retinal findings in children with cerebral malaria (CM) or severe malarial anemia (SMA) appear related to disease outcomes such as prolonged coma and death. Infection of pregnant often leads to abortion; infection of newborn often leads to convulsions and coma. Acute glomerulonephritis (type III hypersensitivity) => malarial hemoglubinuria / blackwater fever (a severe complication of malaria characterized by intravascular hemolysis, hemoglobinuria, acute renal failure, and passage of dark brown or red urine, seen in association with intermittent quinine therapy, with Plasmodium falciparum infection in the nonimmune, or with interrupted exposure in the partially immune. The hemolysis is believed to be caused primarily by an autoimmune response to the infection). It may persist for 2-3 yrs.
Pregnancy-associated malaria (PAM) is responsible for about 2,500 mothers and 300,000 foetuses and infants deaths each year. In PAM var2csa (a member of the PfEMP1 VSA family, var2csa highly conserved and common var gene subfamily lacking both CIDR and DBL-g domains, previously implicated in PfEMP1-mediated adhesion to CD36 and the glycosaminoglycan chondroitin sulphate A (CSA)) is markedly upregulated in parasites and mediates adhesion of iRBC to CSA in the placental intervillous space^ref. Parasites causing PAM express unique VSA types, VSA(PAM), which can be serologically classified as sex specific and parity dependent. It is sex specific because men from malaria-endemic areas do not develop VSA(PAM) antibodies; it is parity dependent because women acquire anti-VSA(PAM) immunoglobulin (Ig) G as a function of parity. VAR2CSA is expressed on the surface of CSA-selected IEs and recognized by endemic plasma in a sex-specific and parity-dependent manner : high anti-VAR2CSA IgG levels can be found in pregnant women from both West and East Africa and women with high plasma levels of anti-VAR2CSA IgG give birth to markedly heavier babies and have a much lower risk of delivering low birth weight children than women with low levels^ref. Vaccinating women against VAR2CSA will give them immunity to infection during pregnancy.
Laboratory examinations : “signet-ring” forms of trophozoites and the “crescent” form of the gametocytes (malarial crescents / flagellated bodies : they may be male (microgametocytes) or female (macrogametocytes))
Therapy^{ref1, ref2} : the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) K76T mutation and haplotype (amino acids 72-76) and the P. falciparum multidrug resistance 1 (Pfmdr1) mutation (N86Y) were analyzed as markers of chloroquine resistance in the DNAs of 73 blood samples from patients with P. falciparum malaria in India. Seventy of the 73 DNAs had the Pfcrt K76T mutation. Of these, 66 had the SVMNT haplotype and 4 had CVIET, the African/Southeast Asian haplotype. Only 20 of 69 DNAs had the Pfmdr1 N86Y mutation. It is surprising that the Pfcrt haplotype in India is predominantly SVMNT, rather than that seen in Southeast Asia. The widespread prevalence of the Pfcrt K76T mutation is a cause for concern^ref. The results should be seen in the context of unconfirmed anecdotes over the past few years that chloroquine and proguanil are no longer effective as prophylaxis in India. If up to 95% of P. falciparum in India has this mutation, chloroquine and proguanil should probably be phased out as malaria prophylaxis in India.
Web resources : Plasmodium falciparum Genome Resource
• Plasmodium knowlesi

Epidemiology : identified in 1931 in a long-tailed macaque, Macaca fascicularis; it is lethal for rhesus monkeys and in 1932 was shown to be infectious to humans by inoculation of infected blood^ref. The parasite was often used in the early 1930s as a pyretic agent for the treatment of patients with neurosyphilis^ref and more recently has been used in analysis of requirements for erythrocyte invasion^ref in vaccine studies^{ref1, ref2} and as a flexible transfection model that allows targeted genetic modification^ref. Currently, the P knowlesi genome is being sequenced^ref. The first natural infection of P knowlesi in a human was reported in 1965 in a man who returned to the USA after visiting peninsular Malaysia. The infecting parasites were first identified in blood films as P falciparum, a day later as P malariae, and only confirmed as P knowlesi after inoculation of infected human blood into rhesus monkeys. There was also a report in 1971 of what was presumed to be a natural infection of a man by P knowlesi in peninsular Malaysia. In this instance, the infecting parasites were initially identified as P malariae and a diagnosis of P knowlesi was based on travel history in the jungle and serological tests, since infected blood was not available for injection into rhesus monkeys^ref. There have been no other published records of naturally acquired P knowlesiinfections in humans despite extensive studies being undertaken in peninsular Malaysia in the 1960s to investigate natural infections of humans by simian malaria parasites, including one that involved transfer of blood from about 1200 human beings to rhesus monkeys^ref. An analysis with nested PCR assay showed that 106 (51%) malaria cases investigated in the Kapit division of Malaysian Borneo (population = 90 697 people; area = 38 934 km², the largest of the administrative divisions in Sarawak) were attributable solely to infection with P knowlesi and 14 (7%) were coinfections of P knowlesi with other Plasmodium species as assessed by nested PCR assay^ref. This large focus of natural P knowlesi infections would have gone unnoticed if we had not used the nested PCR assay, since morphological similarities between P knowlesi and the malaria parasites that infect humans, particularly Plasmodium malariae, make it difficult to correctly identify P knowlesi parasites by microscopy (see RBC inclusions). These morphological similarities have been highlighted by several workers^ref including Garnham who wrote "A P knowlesi infection in a human being could easily pass unrecognised as such in routine laboratories, where it would probably be diagnosed as P malariae, or if rings only were present, as P falciparum.' The P knowlesi-specific primers we have developed can be used to accurately identify P knowlesi infections with the nested PCR assay, which is more sensitive and specific than microscopy for detection of malaria parasites^{ref1, ref2}. However, we do not advocate the use of nested PCR assays for routine diagnosis of malaria since, by comparison with microscopy, PCR detection assays are quite expensive, require specialised equipment, and are not quantitative or rapid. Nevertheless, our study underscores the potential of simple blood spot sampling on filter paper coupled with nested PCR and sequencing in the study of emerging atypical malaria infections in remote areas. The course of infection with P knowlesi, the only primate malaria with a 24-h asexual blood-stage cycle, is dependent on the host. In its natural host, the long-tailed macaque, infection results in prolonged low-level parasitaemia, whereas in rhesus monkeys parasitaemias rise rapidly and the infection is lethal^ref. In human beings, clinical manifestations after experimental transmission by mosquitoes of one strain of P knowlesi varied from moderate to severe; 3 of 5 infected individuals required antimalarial treatment while the remaining 2 spontaneously resolved their infections after 2 weeks^ref. Blood-induced infections in humans with neurosyphilis, where P knowlesi was used as a pyretic agent, also resulted in a range of clinical manifestations from mild infections that resolved spontaneously to those that required antimalarial intervention^ref. In our study, patients who were naturally infected with P knowlesi had the usual symptoms of malaria, they responded successfully to chloroquine and other conventional antimalarials, and there were no deaths reported. Monkey-to-human and human-to-human transmission of P knowlesi by mosquitoes can occur under experimental conditions^ref. Whether the large focus of P knowlesi infections in the Kapit division of Malaysian Borneo is mostly attributable to transmission from human-to-human or monkey-to-human by mosquitoes is not yet known. Mosquitoes of the Anopheles leucosphyrus group are capable of transmitting P knowlesi^{ref1, ref2} and are found in the Kapit division (Matusop A, unpublished observations), as are the natural hosts of P knowlesi, the long-tailed and the pig-tailed macaques. Although these macaques exist in close proximity to humans in the Kapit division and are a potential source of P knowlesi parasites, it has not yet been determined whether they are infected with P knowlesi. Neither the mosquito vector has been identified. P knowlesi infections and those identified as P malariae by microscopy in the Kapit division were mostly in adults and that there was no clustering of cases within longhouse communities suggests that transmission occurs away from the vicinity of longhouses and that monkey-to-human rather than human-to-human transmission is taking place. However, the epidemiological data are only for reported cases of symptomatic infected individuals who sought treatment at the hospital and health clinics. Large-scale molecular epidemiological studies, capable of detecting asymptomatic P knowlesi infections, will shed further light on the possibility of human P knowlesi reservoirs of infection
• Plasmodium malariae
Epidemiology : Medium Eastern, Southern and Western Asia, Central America and Brazil
Symptoms & signs : quartan fever or malaria / malaria quartana (5% of malaria cases) : 18-40 dd. incubation => symptomatology as above, + acute glomerulonephritis due to type III hypersensitivity => nephrotic syndrome, Ziemann granules in RBCs => anemia. Schizogony occurs every 72 hrs, together with fever (crisis defervescence). Relapses dued to hematic latency : it may persist for up to 50 yrs.
Laboratory examinations : bandlike trophozoites and schizonts with 6-12 merozoites usually arranged in a rosette-like configuration.
• Plasmodium ovale
Epidemiology : tropical East and Central Africa, Philipines, New Guinea and Vietnam
Symptoms & signs : benign tertian fever / malaria tertiana / ovale malaria : 15 days-some months incubation => symptomatology as above. Some sporozoites may undergo quiescence in liver (hypnozoites) : it may persist for 4 yrs. Schizogony occurs every 48 hrs, together with fever (crisis defervescence)
Laboratory examinations : oval or fimbriated infected red blood cells.
• Plasmodium vivax
• Plasmodium vivax hibernans
Epidemiology : in Russia and the so-called Newly Independent States and the Scandinavian countries, whose incubation period is 6-8 months, allowing infection in the autumn and a clinical attack the following spring. On April 2004 the 1st case of imported 3-day malaria was registered in Novgorod oblast in a 63-year-old habitant of Borovichekiy region district arrived in Novgorod from Tajikistan on October 2003. The malaria parasites were also discovered during medical assessment of her grandchildren: 2 girls (4 and 8 years old) and a 5-year-old boy. The children are doing well after treatment. The implication is that the children did not visit Tajikistan but were infected at home by the grandmother, yet October temperatures in Novgorod -- which is just south of St Petersburg and in roughly  the same latitude as Stockholm -- would have been too cold for mosquito transmission. However, as last case of autoctonous 3-day malaria was registered in August 2003 in an inhabitant of Novgorod, perhaps there were infected mosquitoes in the city at that time. I am assuming that the grandmother did not donate blood to the 3 children; in some parts of Russia -- and Tajikistan -- outdated therapies such as red cell transfusion "boosters" for sickly children are still in use
Epidemiology : many countries. Imported cases with local transmission in Florida in 2003 (unidentified source^ref) and 2004
• Nepal : the statistics are uncertain, but about 10 000 cases of malaria are reported annually, of which 90% are Plasmodium vivax, which does not cause cerebral (brain) malaria^ref. Almost all cases are reported from the Terai region from below 2000 meters altitude, and the season runs April to October, with peak transmission from June through August. Cerebral malaria develops when Plasmodium falciparum malaria is not treated in time. This can be due to delays by patients and doctors, or may be due to treatment with drugs against which the parasite is resistant. Chloroquine resistance has been reported from Nepal^ref.
Resistance : Duffy blood group (i.e. CD234 / Duffy antigen / Fy-glycoprotein / DARC). Molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria are reliant on Plasmodium-specific Duffy-binding-like domains (DBLs). These cysteine-rich modules recognize diverse host cell-surface receptors during pathogenesis. DBLs of parasite erythrocyte-binding proteins mediate invasion, and those from the antigenically variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) have been implicated in cytoadherence. The simian and human malarial parasites, P. knowlesi and P. vivax, invade human erythrocytes exclusively through the host DARC receptor (Duffy antigen receptor for chemokines). The crystal structure of the P. knowlesi DBL domain (Pk-DBL), which binds to DARC during invasion of human erythrocytes, has been presented. Pk-DBL retains the overall fold observed in DBLs from P. falciparum erythrocyte-binding antigen (EBA)-175. Mapping the residues that have previously been implicated in binding highlights a fairly flat but exposed site for DARC recognition in subdomain 2 of Pk-DBL; this is in sharp contrast to receptor recognition by EBA-175. In Pk-DBL, the residues that contact DARC and the clusters of residues under immune pressure map to opposite surfaces of the DBL, and suggest a possible mechanism for immune evasion by P. vivax. Comparative structural analysis of Pk-DBL and P. falciparum EBA-175 provides a framework for the understanding of malaria parasite DBLs, and may affect the development of new prophylactic and therapeutic strategies^ref
Symptoms & signs : benign tertian fever / malaria tertiana / vivax malaria (40% of malaria cases) : 12 days-some months incubation => symptomatology as above. Schüffner granules in < 2% RBCs => hemolytic anemia. Some sporozoites may undergo quiscence in liver (hypnozoites) for 2-5 years. Schizogony occurs every 48 hrs, together with fever (crisis defervescence) : sometimes a double endoerythrocytary cycle may cause 24 hrs periodicity. It may persist for 2-3 yrs.
Laboratory examinations : ameboid activity and irregular form of its trophozoites
=> intermittent fever : an attack of malaria or other fever characterized by recurring paroxysms of elevated temperature separated by intervals during which the temperature is normal.
The best diagnostic algorithms (history of fever >= 38°C and headache without cough, and history of fever with an oral temperature > or = 38°C [sensitivity 51% for both, specificity 72 and 71%, respectively]) would result in prescription of antimalarial drugs in 28-29% of the non-malaria febrile episodes, and only 49% of the true malaria cases. Thus 51% of the potentially life-threatening P. falciparum infections would not be treated. Although multivariate analysis identified vomiting, confirmed fever, splenomegaly and hepatomegaly as independent risk factors for a diagnosis of falciparum malaria, use of these signs to differentiate falciparum from vivax malaria, and thus to determine antimalarial treatment, was insufficiently sensitive or specific. Malaria diagnosis should be confirmed by microscopical examination of a blood slide or the use of specific dipstick tests in areas of low transmission where highly drug-resistant P. falciparum coexists with P. vivax^ref. During a period of high malaria transmission, 33% of these children had radiological evidence of pneumonia (with or without malaria parasitaemia) compared to 38% who had malaria parasitaemia, no radiological evidence of pneumonia and no other obvious cause of fever. Corresponding figures during a period of low malaria transmission were 48% and 6% respectively^ref.
Laboratory examinations :
• hemoscopy (no hemoculture !), the current 'gold standard', smear microscopy, requires trained technicians and careful quality-control, which is not always possible in the field : it shows :
• RBC inclusions
• rosetting (uninfected RBCs clump together with parasitized RBCs)
• brassy body : a dark, shrunken blood corpuscle
• presegmenting bodies : malarial parasites before they undergo segmentation.
• quantitative buffy coat (QBC)
• spleen or splenic index : the percentage of individuals in the population having enlarged spleens; used in malaria surveys.
• splenometric index : an index of the amount of malarial infection; obtained by multiplying the spleen rate by the size of the average enlarged spleen.
• rapid diagnostic test (RDT) based on detecting^ref :
• malaria parasite protein HRP2 (ParaSight-F and ICT-Malaria Pf^ref) in fingerprick blood were seen to be useful and cost-effective, but are limited because HRP2 proteins circulate for months in the blood after cure and therefore the test cannot distinguish between an old, resolved infection and a new one. Nor do they detect all strains of malaria.
• malaria parasite enzyme pLDH (OptiMAL) in the blood, developed by MSF since 2003. This test is more suited for diagnosing malaria in Africa than the HRP2 test because, among other things, pLDH levels drop rapidly with clearance of parasites, allowing clinicians to distinguish between patients who are still infected with malaria after treatment, and those in whom fever symptoms have another cause. The possibility of a pLDH test was identified by MSF from published papers on the characterization of a panel of pLDH monoclonal antibodies^ref. The entire development process, from identification of diagnostic needs through to field evaluation, was completed in less than 2 years, at the relatively low cost of about 80,000 (US$100,000), most of which went into field trials and was provided by MSF. Development of a new test can typically cost many hundreds of thousands of dollars^ref.
Currently, MSF performs > 4 million malaria RDTs a year, mainly in Africa and Asia. Specific problems with existing tests were previously identified by MSF staff.
Experimental animal models : in mice :
• Plasmodium chabaudi : used to study immune mechanisms and immunoregulation by cytokines, to identify susceptibility loci and to study the immune basis of pathology.
• Plasmodium chabaudi chabaudi AS causes non-lethal infection in resistant mouse strains and lethal infection in susceptible mouse strain
• Plasmodium chabaudi adami causes a mild, non-lethal infection
• Plasmodium berghei : widely used to study pathogenesis
• Plasmodium berghei strain ANKA mouse malaria is and accepted model of the cytokine-dependent pro-inflammatory casacade that develops in human malaria, including experimental cerebral malaria (ECM) : there is genetic variation in the development of ECM between inbred mouse strains, which correlates with the production of pro-inflammatory cytokines.. However, differential expression of NKC loci causes the NKT lymphocytes of C57BL6 mice to promote sustained IFN-g production (T_h1 response) and susceptibility to infection, and the NKT lymphocytes of BALB/c mice to promote a switch from high-level IFN-g to IL-4 production (T_h2 response), which is protective.
• Plasmodium berghei K173
• Plasmodium yoelii : used to study immune mechanisms and pathogenesis, including ECM, as recombinant merozoite surface protein 1 (MSP1) is available.
• Plasmodium yoelii 17XL is widely used to identify vaccine-induced immune responses
• Plasmodium yoelii 17XNL
• Plasmodium yoelii YM.
• Plasmodium vinckei
• Plasmodium vinckei vinckei, which causes a lethal infection, is used to study pathogenesis and for chemotherapy studies
• Plasmodium vinckei petteri, which causes a non-lethal infection, is used to study immune mechanisms
Therapy :
• in high-risk children with severe malaria and acidosis, fluid resuscitation with albumin may reduce mortality^ref
• antimalarial drugs
• artemisin, chloroquine, i.v. quinine and quinidine, primaquine, mefloquine
• pyrimethamine+sulfonamides
• pyrimethamine+dapsone
• triclosan
• doxycycline in cases that are resistant to chloroquine
• arginine, an amino acid that boosts the production of NO^.
• fosmidomycin(466 proteins, or about 10% of the Plasmodium falciparum genome, have transit peptides for apicoplast targeting : due to origin from chloroplast, apicoplast proteins could be targeted by herbicides)
Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi^ref
The opening of the Panama Canal in 1914 initiated an era in which efforts to control malaria were aimed at the anopheline mosquito. The World Health Organization's Global Malaria Eradication Campaign in the 1950s and 1960s marked the apex of these efforts. The use of dichlorodiphenyltrichloroethane (DDT) rid vast areas of endemic malaria virtually everywhere except in sub-Saharan Africa. The eradication strategy was abandoned in 1969, because it came to be considered logistically, socially, and politically impractical, especially given public concern about the effects of DDT on the environment^ref
Resistance of Plasmodium falciparum to chloroquine in nearly all malaria endemic areas over the past 2 decades and the rapid spread of resistance to sulfadoxine-pyrimethamine (the new 1st-line treatment during the past 5 years) has led to strong calls for the introduction of combination treatments^{ref1, ref2}. In 2001, a WHO expert panel recommended use of artimisinin-based combination therapies (ACT)  as first-line treatment for uncomplicated falciparum malaria; once governments had to switch from sulfadoxine-pyrimethamine or chloroquine monotherapy they were advised to use one of three artemisinin-based combinations (sulfadoxine-pyrimethamine+artesunate, amodiaquine+artesunate, artemether-lumefantrine) or a substantially cheaper non-artemisinin-based combination (amodiaquine+sulfadoxine-pyrimethamine). The main obstacle has been the price of these drug combinations. It is most welcome that the price is now within reach of users in Africa^ref. Subsequent trials in various parts of Africa have shown the safety and efficacy of amodiaquine+artesunate^ref and of amodiaquine+sulfadoxine-pyrimethamine^ref, even in areas of moderate resistance to amodiaquine and sulfadoxine-pyrimethamine. Although artemether-lumefantrine is recommended as first-line treatment for uncomplicated malaria in several countries, there is little information about the efficacy of the 6-dose artemether-lumefantrine regimen in African children and the four-dose regimen has not proven efficacious^ref. Sulfadoxine-pyrimethamine+artesunate, chloroquine+artesunate, and chloroquine+sulfadoxine-pyrimethamine were not efficacious in areas with substantial levels of resistance to sulfadoxine-pyrimethamine and chloroquine^{ref1, ref2, ref3}. In addition to safety and efficacy data, information about effectiveness is essential for the formulation of antimalarial drug policy. Efficacious drugs taken under observation in experimental conditions can be much less effective under real-life conditions, especially when complex dosing schedules are needed^ref. Therefore, the effectiveness of 3 drug combinations that have proven efficacy in east Africa, was studied in a trial undertaken in Muheza district, north-eastern Tanzania, which has among the highest recorded levels of resistance to sulfadoxine-pyrimethamine and chloroquine in Africa^{ref1, ref2},  in a clinic setting in which drugs are dispensed and taken at home unobserved by medical staff. The artemether-lumefantrine 6-dose regimen works well in an outpatient setting in areas where the level of resistance to sulfadoxine-pyrimethamine and amodiaquine is high. In this setting, amodiaquine+artesunate worked less well, and amodiaquine+sulfadoxine-pyrimethamine, although significantly better than monotherapy, was not a good treatment option, especially when assessed at the day 28 point. The results of our trial draw attention to the impending malaria treatment crisis in the subregion of east Africa where resistance to chloroquine, amodiaquine, and sulfadoxine-pyrimethamine is established^ref. Combinations of available drugs, such as chloroquine+sulfadoxine-pyrimethamine and chloroquine+artesunate, have not proven effective, even in closely observed efficacy trials in areas where chloroquine resistance is common. Furthermore, sulfadoxine-pyrimethamine+artesunate has been shown to be disappointing in areas where the level of sulfadoxine-pyrimethamine resistance is high^{ref1, ref2, ref3}. Addition of an artemisinin to a failing drug has not proven effective in Africa before and did not seem effective in this trial. The very high rates of reinfection in this part of Tanzania led to day 14 being taken as the primary endpoint, but the day 28 results show a widening difference between the groups and this difference in recrudescence rates probably would have continued even beyond this time. There is considerable, and justified, concern that efficacy data, which are the output from most clinical trials, are not a realistic measure of the effectiveness of a drug in operational practice, especially when dosing regimens are long or complex^ref. Efficacy trials will always give a best-case outcome and there is clear evidence that this is so for antimalarials^ref. When these drugs were taken at home, the six-dose artemether-lumefantrine treatment in WHO packaging was highly effective. A study from Uganda lends support to the results from our trial in showing that adherence to the WHO-packaged drug is reasonable^ref. This trial is much closer to normal outpatient practice than an efficacy trial; however, no effectiveness trial can be an ideal reflection of reality since to obtain data and mimic entirely normal practice is not possible and our results are probably indicative of the most optimistic end of the scale of the effectiveness of the drugs. Additionally, the drugs in our trial were free, and because they are not yet widely known in this area they are not perceived to have a high market value. Pills were therefore unlikely to have been saved and sold on. If the cost or street value of drugs is high, the likelihood of parents completing the course could be adversely affected, which in turn would reduce the effectiveness of this drug combination. The effectiveness of the combination of amodiaquine+artesunate could have been affected by the fact that there is no packaging of this combination for young children and infants. A coformulated version is being developed and might improve adherence, especially if it is well packaged. Appropriate packaging of antimalarials improves adherence^ref and hence probably clinical outcome, although this hypothesis has not been investigated directly. The results obtained with amodiaquine+artesunate in this study are, however, in keeping with some efficacy data from areas of east Africa where amodiaquine resistance rates are high^ref; thus this combination should not be used in areas where resistance to amodiaquine is already high. However, the combination has been shown to be efficacious in areas where resistance to amodiaquine is moderate or low^ref, which is the case in much of west Africa at the moment. Our study suggests the need to test any combination in effectiveness trials with the packaging that will be used in practice before any drug is adopted as national policy. In accordance with results of efficacy studies, artemisinin-containing combinations led to lower gametocyte carriage, suggesting lower infectiousness with these treatments than with other combinations^ref. The amodiaquine+sulfadoxine-pyrimethamine combination, which has been recommended as a short-term or interim strategy before the introduction of an artemisinin-containing combination, has proven efficacious in areas of low to moderate resistance to both drugs even where resistance to chloroquine is high, especially when assessed over long follow-up^{ref1, ref2}. This combination has the major advantage of being cheap, and with better packaging it might be more effective. The rate of failure in this trial suggests, however, that this combination would probably not be useful as treatment for children in areas where parasite resistance to both drugs is high. This failure rate might not be due entirely to the efficacy of the drugs. Parents of children with malaria are likely to be aware that sulfadoxine-pyrimethamine and amodiaquine are failing in this area, and this factor could reduce adherence. The options are for antimalarial treatment in children in the parts of east Africa where levels of resistance are high are very limited. The artemether-lumefantrine combination works at present, although the long half-life of lumefantrine might make this combination vulnerable to selection pressure. The cost of the drug means that it is likely to reach only a fraction of those who need it, unless the price is substantially reduced either through market mechanisms or (more realistically) through subsidy^ref. Supply is currently a major problem. This situation is likely to be exacerbated by the fact that malaria is over diagnosed and therefore a substantial proportion of malaria treatment given is for individuals who do not in fact have the disease^{ref1, ref2}. Drug combinations that can help to fill the gap in the medium term are being developed, of which piperaquine-dihydroartemisinin^ref and chlorproguanil-dapsone-artesunate are among the most promising. Chlorproguanil-dapsone can be effective where sulfadoxine-pyrimethamine has failed^ref. None of the artemisinin combinations is cheap, and this is a serious limitation; addressing this issue in a sustainable way will not be easy. Current efforts by the Global Fund and others will provide cheap artemisinin-containing combinations for several countries, but it is too early to assess the sustainability and scope of these efforts. Our study shows that in areas where chloroquine, amodiaquine, and sulfadoxine-pyrimethamine have failed badly, use of any of these drugs in combination is unlikely to work^ref.
Several studies have documented an increase in the incidence of clinical malaria in children after prophylaxis stopped--the so-called rebound effect^ref. In a safety and efficacy trial of intermittent antimalarial preventive treatment in infants^ref, sulfadoxine-pyrimethamine delivered at the time of routine vaccinations reduced the incidence of clinical malaria by 59% (95% CI 41-72), and halved the incidence of severe anaemia (defined by a packed cell volume <25%) in the first year of life : a 2-year follow-up excluded any rebound effect after this treatment and suggested that such treatment could facilitate development of immunity against Plasmodium falciparum^ref.
Prevention : in 1998, the WHO launched the Roll Back Malaria (RBM) initiative, which set the target of halving world malaria deaths by 2010.
• subunit vaccines
• chemoprophylaxis : the WHO performed an interesting study in 1971, the Garki project, in Nigeria, trying to control malaria by continuous chemoprophylaxis and residual spraying against mosquitoes. Parasite rates were brought down from over 50% to below 0.2%, but returned to pre-project levels within 3 years when the project was terminated. Another test will be performed in 2007 delivering a a single dose of arteminisin-based combination therapy (ACTs) and primaquine to all 40000 inhabitants of Moheli Island, Comoro Islands. Because infected mosquitoes -- which have a 30-day life span -- may still be lurking and transmit the disease, a 2nd round of mass drug intake will be carried out 40 days later. While the average carrier rate in the 10 most seriously affected villages on Moheli is 50%, the rate is as high as 94.4% in some villages and as low as 6.5% in other areas. Malaria is the most common cause of death for children under the age of 5^ref. The Comoros archipelago has a high prevalence of red cell genetic disorders, such as G6PD (glucose 6 phosphatedehydrogenase) deficiency and some hemoglobinopathies. Has this high prevalence been considered ahead of wide distribution of primaquine without G6PD dosage? The theoretical risk for hemolysis should be considered. What dose schedule of primaquine is to be used? Country list; Vaccination requirements and

malaria situation. In: International travel and health publication. Geneva: World Health Organization; 2005^ref
• insect repellents
• insecticide treated bed nets (ITN) can reduce transmission of malaria by 17% and are a priority for pregnant women (only 4% of Africa's children sleep under one each night)
• engineering lab mosquitoes to contain a gene that stops the malaria parasite from completing its life cycle in their guts and salivary glands. The malaria-proof insects would then be set free. To help the gene spread during mating, another gene - a transposon - is inserted alongside. ut wild mosquitoes swamped these insects. After only 4 generations - equivalent to just 1 summer in many parts of Africa - none of the inserted genes could be detected. One solution might be to mate transgenic mosquitoes with wild ones and select those that retain the malaria-resistance genes in the lab, before releasing the insects into the wild. This might make the manipulated insects tough enough to dominate their wild cousins
• Malaria Early Warning Systems, using weather forecasting and data on malaria hotspots, must be created to help authorities mitigate outbreaks. Such systems are already proving their worth in South Africa and are on trial in other countries.
• by linking the distribution of malaria-prevention measures with the delivery of drugs, vaccines and clean water, health projects can pool their resources. Molyneux and Nantulya point to the success of a recent trial in Zambia and Ghana, in which children being immunized against measles were also given insecticide-treated bednets to protect them from the mosquitoes that carry malaria. Within a week, the region had achieved one of Roll Back Malaria's goals: it ensured that 60% of children and pregnant women sleep under a net : the additional cost to the measles trial would be just 32 US cents a bednet. This is a small addition to the US$3 cost of a net and a small price to pay to overcome the logistical problems that currently hinder the malaria initiative. The idea could be put to wider use in conjunction with efforts to combat lymphatic filariasis, a mosquito-transmitted disease with a similar distribution to malaria. Albendazole, one of the drugs used to tackle filariasis and subsidized by GlaxoSmithKline in Africa, also helps to control the hookworms that cause anaemia in many rural African communities. And reducing anaemia could make people less vulnerable to malaria
Malaria costs Africa an estimated $12 billon/year in lost gross domestic product.
The Bill and Melinda Gates Foundation is backing an ambitious project with the Zambian government to reduce deaths from malaria by three-quarters in just three years. They plan to use existing controls such as bednets, drugs, and house spraying on a much wider scale than ever before.  The new project is known as Malaria Control and Evaluation Partnership in Africa (MACEPA), and will be run by the Seattle-based non-profit organization PATH with a 9-year US$35 million grant from the Gates Foundation. Zambia government has pledged to provide insecticide-treated nets for 90% of households, and to ensure that 60% of patients get treated with antimalarial artemisinin drugs within 24 hours. It also hopes to provide prophylactic drugs for 90% of pregnant women, who lose their naturally acquired immunity to severe malaria during pregnancy. MACEPA will also work with the UN-led Roll Back Malaria Partnership; the Global Fund to Fight AIDS, Tuberculosis, and Malaria; and the World Bank. Roll Back Malaria, established in 1998, has pledged to cut malaria deaths worldwide by 50% by 2010, but it is far off track because international efforts have been too fragmented. Monitoring the effectiveness of its campaign will be a high priority : clear evidence of their success will guide large-scale efforts in other nations. More money has recently become available to tackle the disease, and a flagship campaign like MACEPA could help to make best use of the funds. The Global Fund has currently pledged $949 million over 2 years for malaria control, for example, and this may rise to $1.83 billion over 5 years. Of this, Zambia has been allocated $38 million over 2 years, and may get as much as $83 million over the next 5 years. The project will also measure the economic impact of reducing deaths. Given that disease is a major cause of poverty, the partnership hopes its figures will prove to governments that public health improvement can substantially boost a nation's economic performance. Malaria is estimated by the World Bank to cut the economic growth of African countries by at least 1.3% annually. It was the social and economic impact of malaria, which is responsible for 40% of child deaths in Zambia, that had prompted his government to make malaria control a priority.
Web resources :
• Malaria genetics and genomics at NCBI
• WHO/TDR Malaria Database
• WHO : Health topics : malaria and Roll Back Malaria (RBM)
• The Africa Malaria Report WHO/CDS/MAL/2003.1093
• Malaria: diagnosis, prophylaxis, treatment and history
• Nature Publishing Group : Malaria special and Malaria outlook at Nature and Nature Science Update
• Malaria Foundation International
• PlasmoDB : The Plasmodium Genome Resource
• Global Fund to fight AIDS, tuberculosis and malaria
• Journals : Malaria Journal
• Medicines for Malaria Venture (MMV)
• Malaria Research and Reference Reagent Resource Center (MR4)
• Multilateral Initiative on Malaria

Malaria news


Bibliography :
• Medical geography - Geography of malaria by Lysenko AY, Semashko IN
• The Intolerable Burden of Malaria: II. What's New, What's Needed. Breman, Joel G.; Alilio, Martin S.; Mills, A., editors Cleveland (OH): The American Society of Tropical Medicine and Hygiene; ©2004 [Free at NCBI Bookshelf ! ]
• [Piroplasmia : a subclass of heteroxenous parasitic protozoa (class Sporozoea, subphylum Apicomplexa), occurring as piriform, round, or rod-shaped cells or ameboid cells without a conoid, oocysts, spores, pseudocysts, and flagella, and usually without subpellicular microtubules but with a polar ring and rhoptries. Locomotion is accomplished by flexion, by gliding, or, in sexual stages of certain species, by large axopodium-like organelles (strahlen). They are parasitic in the erythrocytes and other circulating and fixed cells of the host, with merogony occurring in vertebrates and sporogony in invertebrates, and producing sporozoites with a single-membraned wall. Ticks are the vectors of most of the piroplasmids. It comprises a single order :]
• Piroplasmida. Representative genera include :
• Cytauxzoon
• Dactylosoma
• Theileria
• Babesiidae
• Babesia (a.k.a. Babesiella and Piroplasma) : a genus of protozoa of the order Piroplasmida, occurring as single or paired parasites within the erythrocytes of various vertebrates, causing babesiosis and other diseases in domestic and wild animals and humans and transmitted by ticks, in which a sexual multiplicative cycle occurs. Certain species have been reported to cause a malarialike disease in both healthy and splenectomized individuals
• Babesia bovis
Epidemiology : Central and South America, certain regions in Europe, North, Central, and South Africa, the Middle East, the West Indies, and formerly the southern United States
Transmission : reservoir : Bos taurus; vector : Boophilus annulatus and Boophilus microplus are the chief vectors but in some areas Ixodes ticks are vectors
• Babesia canis

Transmission : in Europe the 3 subspecies/subtypes are transmitted by Dermacentor and Rhipicephalus tick species, mainly Dermacentor reticulatus and Rhipicephalus sanguineus (the common or brown dog tick).
• Babesia divergens
Epidemiology : France and Spain
Transmission : reservoir : Bos taurus; vector : Ixodes ricinus
• Babesia microti
Epidemiology : in the USA the infection is endemic in the Northeast and upper Midwest, although cases have recently been described in Northern California and Washington State
Transmission :
• reservoir : Rodentia and Canis familiaris; vector : Ixodes dammini
• under blood banking conditions (4°C for 30 days), it can remain infective and that transfusion-acquired infection with this parasite could occur during the normal storage time for blood.
the new isolate European Union 1 (EU1) is most closely related to but distinct from Babesia odocoilei, which infects white-tailed deer. The first known human cases of babesiosis in Italy and Austria occurred in 55  and 56 year old men, respectively, who had undergone splenectomy in the 1980s because of stage IA Hodgkin's disease. The Italian patient had recently begun chemotherapy for stage IIIA diffuse large B cell lymphoma, which had been diagnosed in June 1998. Both men lived in small towns and hunted avocationally; neither had pets. Only the Austrian patient recalled tick exposure, a tick bite while hunting about 2 weeks before he noticed his urine was dark. Neither patient had travelled extensively: the Italian patient had never left Italy, and the Austrian patient had been in Barbados (1998) and Turkey (1999).The 2 cases ranged in severity from quite mild (Austrian case) to moderately severe (Italian case). Fever occurred only in the Italian patient (maximum of 39°C), which initially was considered a reaction to one of his chemotherapeutic agents (bleomycin). He also had marked anemia, for which he received blood transfusions. Both patients had thrombocytopenia, elevated serum LDH and bilirubin values, and hemoglobinuria. The Italian patient's creatinine value also was elevated.
=> babesiosis / babesiasis / piroplasmosis after 1-4 weeks incubation : self-limiting infection of RBCs (1-90% are parasitized) with a duration of weeks to months : irregular malarialike fever with chills, nausea and vomiting, diaphoresis, headache, moderate hemolytic anemia => hemoglobinemia, myoarthralgia and fatigue, liver failure (jaundice and hepatomegaly), splenomegaly and hemoglobinuria => acute renal failure. Although many infections seen in the northeastern United States are subclinical, infections in California and Europe tend to present as a fulminant, febrile, hemolytic disease affecting splenectomized or immunosuppressed individuals. Any person with babesiosis acquired in Europe should be treated on an emergency basis. They should receive prompt specific therapy to reduce parasitemia and to prevent extensive hemolysis and potential renal failure. A rapidly increasing parasitemia characterized by infections with B. divergens may require massive exchange transfusion
Laboratory examinations : serological testing of acute and convalescent sera, examination of a May-Grunwald Giemsa-stained rather than Wright-stained peripheral blood smear, xenodiagnosis by injecting specimens of blood intraperitoneally into a hamster or gerbil (however, not all Babesia species will infect these animals : in many cases, the organisms can be demonstrated within a few days, with the same parasite morphology as that seen in humans), and PCR on whole blood (analytical sensitivity of the system is approximately 3 merozoites^ref) should be done to confirm the diagnosis of babesiosis and a response to treatment
Therapy : clindamycin + quinine (for HIV-infected and other immunocompromised patients, clindamycin and quinine should be given for longer than 7-10 days in order to minimise the risk of relapse). When left untreated, silent babesial infection may persist for months or even years. Although treatment with clindamycin and quinine reduces the duration of parasitemia, infection may still persist^ref and recrudesce and side effects are common. Improved treatments are needed : all immunocompromised patients^ref should have convalescent blood samples checked for persistent or recurrent parasitaemia in the months after treatment. The use of azithromycin in combination with quinine may be considered as an alternative therapy.
Prevention : the most common approach used to protect humans from infection involves methods to reduce the tick density, including spraying of vegetation. Repellents can be helpful for personal protection, however, daily examination of the body surface of a person who may have come in contact with ticks is critical. If ticks are found, they should be removed immediately to take advantage of the lag time between attachment to the human and transmission of the infection (usually 50 to 60 hours).
• Ciliophora (ciliates) : a phylum of protozoa characterized by the presence of cilia or compound ciliary structures as locomotor or food-gathering organelles at some time during their life cycle, a subpellicular infraciliature composed of ciliary basal bodies and kinetodesmata (even when cilia are absent), and two types of nuclei, a macronucleus and a micronucleus (with rare exceptions); a contractile vacuole is typically present. Sexuality involves conjugation, autogamy, and cytogamy. Most ciliophorans are free living, many are commensals of vertebrates and invertebrates, and some are parasites. The phylum comprises 4 classes :
• Kinetofragminophorea : a class of ciliate protozoa (phylum Ciliophora), characterized by the presence of isolated kineties in the oral region of the body (kinetofragments) bearing cilia but not compound ciliary organelles; a cytostome and cytopharyngeal apparatus are often present. It comprises 4 subclasses:
• Gymnostomatia
• Vestibuliferia : a subclass of free-living or parasitic (especially in the digestive tract of vertebrates and invertebrates) ciliate protozoa, characterized by the presence of a cytosome within a groove (vestibulum) bearing distinct ciliature at or near the apical end of the body and a cytopharynx. It comprises 3 orders:
• Trichostomatida
• Entodiniomorphida
• Colpodida
• Hypostomatia
• Suctoria
• Litostomatea
• Trichostomatia [Trichostomatida : an order of ciliate protozoa (subclass Vestibuliferia, class Kinetofragminophorea), many of which are endocommensals in vertebrates; most have uniform somatic ciliature, sometimes asymmetrical, and no buccal ciliature in the oral region is present. It comprises 2 suborders: Trichostomatina (in which the somatic ciliature is not reduced) and Blepharocorynthina (found in herbivorous mammals, especially horses, and characterized by a marked reduction in somatic ciliature and apically by a retractable oral area, prominent frontal lobe, and a distinctive corkscrew-like process)]
• Vestibuliferida
• Balantidiidae
• Balantidium a genus of ciliate protozoa of the order Trichostomatida, suborder Trichostomatina, including many species found in the intestines of vertebrates and invertebrates.
• Balantidium coli : the largest protozoan and the only ciliate parasite of humans, which is also found in pigs and monkeys; it may measure 30 to 150 mm long by 25 to 120 mm wide.

Transmission : a zooanthroponosis from Sus scrofa, Rattus norvegicus
=> balantidiasis / balantidosis / balantidiosis : ulcers of cecum and large intestine => acute dysentery, nausea and vomiting, anorexia, asteny, abdominal pain, tenesmus, no fever. Chronic colitis : 8-10 diarrhea movements per die alternated to constipation. Complications : perforation (=> peritonitis), liver abscess, urogenital localizations
Chemotherapy : oxytetracyclin, metronidazole and albendazole.
• Balantidium suis : a nonpathogenic species found in pigs considered by some to be identical with B. coli and by others to be a separate species.
• Oligohymenophorea : a class characterized by the presence of an oral apparatus that is usually well developed and situated at least partially in a buccal cavity and by oral ciliature that is clearly distinct from the somatic ciliature, consisting of a paraoral membrane on the right side and a few compound organelles on the left. Some species are loricate, and colony formation is common in some groups. It comprises two subclasses:
• Hymenostomatia : a subclass of chiefly freshwater, ciliate protozoa with uniform, heavy body ciliature and a ventral buccal cavity when one is present; if kinetodesmata are present, they are usually conspicuous. It comprises 3 orders:
• Hymenostomatida : an order of ciliate protozoa characterized by the presence of a well-defined buccal cavity containing membranelles or peniculi with infraciliary bases typically three to four rows of kinetosomes wide; and by a ventral oral area, usually in the anterior half of the body. It comprises 3 suborders:
• Ophryoglenina : a suborder of large, chiefly freshwater, histophagous ciliate protozoa, characterized by a polymorphous life cycle and an oral apparatus including three ciliary organelles on the left and an associated watchglass organelle on the right. Several species cause disease in marine and freshwater fish, resulting in great economic loss
• Ichthyophthirius
• Ichthyophthirius multifiliis

=> "ich" or white spot disease / ichthyophthiriasis in marine and freshwater fishes : penetration by tomites causes irritation, mucus production, hyperplasia, white pustules, sloughing of epithelium, death
• Peniculina
• Tetrahymenina
• Scuticociliatida
• Astomatida
• Peritrichia : a subclass of typically cone-shaped, ciliate protozoa, characterized by the presence of a prominent oral ciliary field covering the apical end of the body and spiraling counterclockwise into the infundibulum, a paroral membrane and adoral membranelles that become peniculi, and much reduced somatic ciliature. Many are stalked and sedentary, and others are mobile, all with an aboral scopula. The free-swimming larvae have a locomotory posterior ciliary girdle. It comprises 1 order:
• Peritrichida : an order of ciliate protozoa (subclass Peritrichia, class Oligohymenophorea) having characters of the subclass. It comprises 2 suborders:
• Sessilina
• Mobilina
• Polyhymenophorea
• Dinophyceae
• unclassified Dinophyceae
• Pfiesteria

=> human pfiesteriosis :
• Pfiesteria piscicida and look-alike dinoflagellates are collectively known as Pfiesteria complex organisms (PCOs) / toxic Pfiesteria complex (TPC) (Pfiesteria shumwayae) : they are estuarine dinoflagellates thought to be responsible for massive fish deaths along the mid-Atlantic coast in 1992 and associated human illnesses in the southeastern United States. These dinoflagellates are described as having a complex life cycle involving flagellated zoospores, cysts, and amoeboid stages. Although no Pfiesteria toxin has been identified, certain strains of these dinoflagellates are thought to produce a water-soluble toxin that can kill fish and cause human illness. Recent reports show no evidence for amoeboid stages and indicate that a much more simplified life cycle exists. In addition, researchers have shown that P. shumwayae only kills fish through direct contact that does not necessarily involve the production of one or more toxins^ref.

=> possible estuary-associated syndrome (PEAS) :
• in December 1993, a patient presented with significant cognitive deficits 2 weeks after ceasing occupational laboratory exposure to cultures and toxin(s)^ref. He exhibited a variety of symptoms, including reversible cognitive impairment, decreased visual contrast sensitivity (VCS) and loss of short-term memory. Acute high-level exposures to waterways where Pfiesteria has been identified have been linked with eye and respiratory irritation, headache, and gastrointestinal complaints.
• in 1997, adverse effects have been reported in watermen exposed to aerosols of water containing P piscicida on the Pocomoke River in Maryland : neurocognitive function of affected persons improved after 2 weeks of treatment with cholestyramine and returned to within normal ranges within a period of 3-6 months. Persons with the most severe neurocognitive deficits were significantly more likely to have skin lesions characterized on biopsy by evidence of a toxic/allergic inflammatory reaction
• Heterolobosea
• Schizopyrenida : an order of cylindrical, monopodial, typically uninucleate ameboid protozoa (subclass Gymnamoebia, class Lobosea), some species of which exhibit temporary flagellate stages during their life cycle
• Vahlkampfiidae
• Naegleria [F.P.O. Nägler, Austrian bacteriologist, 20th century]  a genus of free-living protozoa found in fresh water, soil, and sewage, which have both an ameboid and a flagellate stage in their life cycle; in the latter stage, 2 flagella are present

=> naegleriasis
• Naegleria australiensis
• Naegleria fowleri

Transmission : inhalatory infectionin young persons who swim or bathe in contaminated stagnant water, the pathogens gaining access to the CNS by penetrating the nasal mucosa and cribriform plate and then following the olfactory bulbs and nerves to the brain and meninges
=> primary amebic meningoencephalitis (PAM) after 5-7 days incubation :
• acute and highly fatal CNS infection in otherwise healthy persons
• granulomatous amebic encephalits (GAE) infection in immunocompromised persons => death by heart failure.
• Vahlkampfia : a genus of freshwater or parasitic ameboid protozoa, characterized by the presence of one broad pseudopodium
• [Sarcomastigophora : a phylum comprising protozoa that typically possess an endosome nucleus characterized by a ring of nuclear chromatin around a central chromatin-free region, and are motile by means of flagella, pseudopodia, or both types of locomotor organs. The phylum includes the subphyla
• Mastigophora / Euflagellata / Flagellata : a subphylum of protozoa comprising the flagellates, i.e., all those with one or more flagella in the trophozoite. Mastigophorans have a simple, centrally placed nucleus and reproduce by longitudinal binary fission, and most are free-living but many are parasitic in both invertebrates and vertebrates, including humans. The subphylum comprises 2 classes :
• Phytomastigophorea (plantlike protozoa, or phytoflagellates)
• Zoomastigophorea (animal-like protozoa, or zooflagellates)
• Sarcodina (amebae) : a subphylum of protozoa, the organisms of which alter their body shape and move about and acquire food by extension of cytoplasmic organelles (pseudopodia) of various types, or by protoplasmic flow without producing discrete pseudopodia. Some have flagella during developmental or other temporary stages. The body of some sarcodines is naked, while in others an external or internal test or skeleton is present. It comprises 2 superclasses :
• Rhizopoda : a superclass of protozoa, comprising the amebae, which move about and acquire food by means of filopodia, lobopodia, or reticulopodia, or by protoplasmic flow without production of discrete pseudopodia. The majority are free-living in soil and water, but some are parasitic and pathogenic in humans. It comprises 8 classes :
• Lobosea
• Acarpomyxea
• Acrasea
• Eumycetozoea
• Plasmodiophorea
• Filosea
• Granuloreticulosa
• Xenophyophorea
• Actinopoda
• Opalinata (opalinids) : a subphylum of parasitic, flat, leaf-like, multinucleate protozoa found as endocommensals in anurans and less often in fish, salamanders, and reptiles. They have cilia arranged in multiple oblique longitudinal rows over the entire body surface, but differ from the Ciliophora in that they possess only one type of nucleus (i.e., no differentiated micronuclei and macronuclei) and they reproduce sexually. It comprises one class:
• Opalinatea : a class of parasitic ciliated protozoa with characters of the subphylum. It comprises 1 order:
• Opalinida : a genus of ciliate parasitic protozoa found as endocommensals in the colon of frogs and toads. The life cycle of O. ranarum involves asexual reproduction in adult frogs and sexual reproduction in tadpoles
• Lobosea : a class of ameboid protozoa (superclass Rhizopoda, subphylum Sarcodina) typically characterized by the presence of lobopodia, although filopodia or reticulopodia sometimes occur. It comprises 2 subclasses:
• Gymnamoebia
• Testacealobosia
• Euamoebidae
• Hartmanellidae
• Hartmanella : a genus of free-living protozoa found in fresh water and soil, species of which are capable of facultative parasitism

=> hartmannelliasis
• Hartmannella hyalina
• Hartmanella vermiformis
=> hematogenous spread => bronchopneumonia and primary amebic meningoencephalitis (PAM) => endocranial hypertension => coma and death especially in the immunocompromised host. It can harbor Legionella pneumophila.
• Leptomyxida : an order of ameboid protozoa (class Acarpomyxea, superclass Rhizopoda) typically occurring in thin protoplasmic sheets that are sometimes polyaxial and sometimes cylindrical. Representative genera include Leptomyxa and Rhizamoeba.
• Leptomyxidae
• Balamuthia
• Balamuthia mandrillaris

=> opportunistic infections from stagnant water (cutaneous ulcers, conjunctivitis (expecially in contact lenses carriers) ==olfactory nerve (?)==> chronic primary amebic meningoencephalitis (PAM) in both immunocompromised and previously healthy patients; some cases are fatal

• Chilomastix : a genus of pear- or lemon-shaped parasitic protozoa (order Retortamonadida, class Zoomastigophorea), having three flagella and a single nucleus, beside which the cytostome is located, and found in the intestines of various vertebrates, including humans. All species are considered nonpathogenic or only slightly so, but one species, C. mesni¢li, has been associated with rare cases of watery diarrhea.
• Chilomastix mesnili

=> commensal intestinal amoeba
=> chilomastigiasis / chilomastixiasis
• Iodamoeba buetschlii

Transmission : reservoir : primates, Sus scrofa.
=> commensal intestinal amoeba

They all cause 50% of deaths before age 5 (15 millions / yr)

• Nature Insight Malaria in Nature Vol.415, 7 February 2002

• Medical protozoology course at Tulane University
• Parasitology Section of Microbiology and Immunology On-line
• Parasites and Parasitological Resources

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