Table of contents :

  • Epidemiology
  • Genomics
  • Proteomics
  • Transmission
  • H1
  • H1N1
  • H1N7
  • H2
  • H2N2
  • H2N3
  • H2N8
  • H2N9
  • H3
  • H3N1
  • H3N2
  • H3N8
  • H4
  • H5
  • H5N1
  • H5N2
  • H5N3
  • H5N9
  • H6
  • H7
  • H7N1
  • H7N2
  • H7N3
  • H7N7
  • H7N9
  • H8
  • H9
  • H9N2
  • H9N2
  • H10
  • H10N8
  • H11
  • H12
  • H13
  • H14
  • H15
  • H16
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Therapy
  • Prevention
  • Web resources

  • Epidemiology : first described by Hippocrates in 412 b.C.. Different strains also infect Aves spp. (chickens, turkeys, ostriches (various AI virus strains have been isolated in recent years from clinically affected ostriches, in several countries. All but one were not poultry-pathogenic : the only reported clinical outbreak in ostriches caused by a poultry-pathogenic strain (HPAI) was recorded in Italy (H7N1)ref), quail, and peacocks; aquatic species : ducks, geese), Sus scrofa, Equus caballus, Phocidae, mustelids and Bos taurusref. Although viruses of relatively few subtype combinations have been isolated from mammalian species, all subtypes, in most combinations, have been isolated from birds.

    Genomics : 8 RNA segments. NIAID will invest $1 million to $2 million annually to sequence 500-1,000 influenza strains a year, each of them > 13,000 genetic letters long. The next step is to consult with scientists about which strains they would like to begin with and how to prioritize them. Robert Webster of St Jude Children's Research Hospital in Memphis, Tennessee, for example, is involved in the sequencing project and has a repository of over 12,000 bird flu strains collected over 27 years.
    Proteomics : 10 proteins + 1 facultative product
    Inside each envelope is a viral genome consisting of 8 negative-sense ssRNA segments of 890 to 2,341 nucleotides each. These segments are associated with nucleoprotein and 3 polymerase subunits, designated PA, PB1 and PB2; the resultant ribonucleoprotein complexes (RNPs) resemble a twisted rod (10–15 nm in width and 30–120 nm in length) that is folded back and coiled on itself. Late in viral infection, newly synthesized RNPs are transported from the nucleus to the plasma membrane, where they are incorporated into progeny virions capable of infecting other cells. TEM of serially sectioned virions shows that the RNPs of influenza A virus are organized in a distinct pattern (7 segments of different lengths surrounding a central segment). The individual RNPs are suspended from the interior of the viral envelope at the distal end of the budding virion and are oriented perpendicular to the budding tip. This finding argues against random incorporation of RNPs into virions, supporting instead a model in which each segment contains specific incorporation signals that enable the RNPs to be recruited and packaged as a complete set. A selective mechanism of RNP incorporation into virions and the unique organization of the eight RNP segments may be crucial to maintaining the integrity of the viral genome during repeated cycles of replicationref.
    Avian influenza viruses have adapted to human hosts causing pandemics in humans. The key host-specific amino acid mutations required for an avian influenza virus to function in humans are unknown. Through multiple sequence alignment and statistical testing of each aligned amino acid we identified markers that discriminate human influenza viruses from avian influenza viruses. We applied strict thresholds to select only markers which are highly preserved in human influenza isolates over time. A subset of these persistent host markers exist in all human pandemic influenza sequences from 1918, 1957 and 1968, while others are acquired as the virus becomes a seasonal influenza. Human H5N1 influenza viruses are significantly more likely to contain the amino acid predominant in human strains for a few persistent host markers when compared to avian H5N1 influenza viruses. This sporadic enrichment of amino acids present in human-hosted viruses may indicate that some H5N1 viruses have made modest adaptations to their new hosts in the recent past. The markers reported here should be useful in monitoring potential pandemic influenza viruses. The researchers discovered these markers by computationally surveying the sequence of amino acids in 10,671 proteins from avian influenza viruses and 13,757 proteins from human influenza viruses. The survey identified 32 persistent markers that exist in five bird and human virus proteins: PA, NP, M1, NS1 and PB2. These markers stand out as obvious differences between bird and human viruses, and many appear in regions where host protein and viral replication occur. The researchers did not determine what functional role the markers play in the life of the viruses. For example, 26 of the 32 markers discovered are found in NP, PB2 and PA, which help to form a complex of proteins critical for the replication of virus genes. The other six persistent host markers are in M1 and NS1 proteins. M1 is known to bind to a protein in cells that enhances the replication of viruses; and NS1 plays a role in suppressing the host immune response. Therefore, the markers in M1 and NS1 might represent key mutations needed to improve the ability of the virus to suppress the immune system and enhance viral replication. The St. Jude team also studied markers in influenza viruses that caused pandemics in 1918, 1957 and 1968—outbreaks thought to have been caused by avian influenza viruses that adapted to humans. The study focused on the viruses isolated from humans early in each pandemic in order to determine which markers the viruses had recently acquired just before they sparked the outbreak. The researchers showed that 13 of the 32 markers identified by their survey had remained stable in these viruses, and, like the other viruses, these markers were distributed among PB2, PA, NP and M1—the proteins linked to virus replication. This suggests that these 13 sites are required for pandemic influenza to fully function. The researchers also showed that the H1N1 virus that caused the 1918 pandemic—the most deadly pandemic known—already contained 13 of the 32 markers early in the outbreak; and acquired the other 19 markers within 10 to 20 years, acquiring the preferred human influenza amino acids in stages. Eventually, descendents of the pandemic virus became the seasonal flu outbreaks rather than deadly pandemicsref.
    Transmission : respiratory route. Human influenza virus replicates mainly in the upper respiratory tract and is usually readily transmitted via droplets formed during coughing or sneezing (B. R. Murphy, R. G. Webster, in Fields Virology, B. N. Fields et al., Eds. (Lippincott-Raven, Philadelphia, 1996), vol. 1, ch. 46). By contrast, the H5N1 influenza virus typically infects human cells in the lower respiratory tractref1, ref2 and so may be less easily shed from the infected patient; this may partly explain why so far there has been little human-to-human transmission observed.
    Epidemiology : during February–May 2013, the initial outbreak of human infection in China resulted in 133 casesref. Influenza A(H7N9) virus reemerged in southern China in October 2013 and had caused 85 laboratory-confirmed cases of infection in Guangdong Province as of March 7, 2014. Targeted surveillance for influenza A(H7N9) identified 24 cases of infection with this virus in Guangzhou, China, during April 1, 2013–March 7, 2014. The spectrum of illness ranged from severe pneumonia to asymptomatic infectionref. It is unclear how the H7N9 virus re-emerged and how it will develop further; potentially it may become a long-term threat to public health. H7N9 viruses have spread from eastern to southern China and become persistent in chickens, which has led to the establishment of multiple regionally distinct lineages with different reassortant genotypes. Repeated introductions of viruses from Zhejiang to other provinces and the presence of H7N9 viruses at live poultry markets have fuelled the recurrence of human infections. This rapid expansion of the geographical distribution and genetic diversity of the H7N9 viruses poses a direct challenge to current disease control systems. H7N9 viruses have become enzootic in China and may spread beyond the region, following the pattern previously observed with H5N1 and H9N2 influenza virusesref
    Epidemiology : In China, H10N8 virus was isolated from the environment of Dongting Lake in Hunan Province in 2007ref and from a duck in a live poultry market (LPM) in Guangdong Province in 2012ref. This AIV was not then known to directly infect humans or other mammals. In December 2013, H10N8virus infection in a person was reported in Nanchang, Jiangxi Province, Chinaref; 2 more human cases followedref1, ref2. The initial reported case was in a 73-year-old woman who visited a local LPM 4 days before the onset of her illnessref. The emergence of the novel influenza A(H10N8) virus has become an urgent public health concernref1, ref2. A preliminary genomic analysis showed that the emerging influenza virus was genetically distinct from the avian influenza A(H10N8) viruses previously identified in China, and scientists have postulated that the virus resulted from multiple reassortments of subtype H9N2 strains that circulated widely in poultry in Chinaref. The virus was conserved in chicken eggs but presented substantial adaptive mutations in MDCK cellsref
    Susceptibility : humans who had previously encountered an influenza virus with the N2 neuraminidase may have been partially protected in the 1968 H3N2 pandemic that followed the global circulation of H2N2 virusesref. There is also indirect evidence of short-term immunity between subtypes of influenza virusesref (Y. Xia, J. R. Gog, B. T. Grenfell, Appl. Statist. 54, 659 (2005)), which could play a role in the early spread of pandemicsref. In addition, cross-reactive T cells also may contribute to heterosubtypic immunity to influenza and reduce viral sheddingref.
    Pathogenesis : during the course of a single-cycle infection, human viruses preferentially infected non-ciliated cells, whereas avian viruses, as well as the egg-adapted human virus variant with an avian virus-like receptor specificity, mainly infected ciliated cells. This pattern correlated with the predominant localization of receptors for human viruses (a2-6-linked sialic acids) on non-ciliated cells and of receptors for avian viruses (a2-3-linked sialic acids) on ciliated cells. These findings suggest that although avian influenza viruses can infect human airway epithelium, their replication may be limited by a non-optimal cellular tropismref. The influenza virus hijacks receptor-based endocytosis to invade a cell, moving from early endosomes through to late endosomes before fusing with the endosomal membrane to release its genetic material. This complex process is thought to involve 2 pH changes, one from extracellular pH to early endosome pH (~pH 6) and a second change to late endosomal pH (~pH 5), with the late pH change an absolute requirement for influenza fusion. The trajectory from the cell periphery, moving to the perinuclear region and finally fusing with a late endosome follows a previously unknown 3-step pattern: the virus tracks slowly in a actin dependent manner through the cell periphery (stage I), increases in speed in a microtubule dependent manner (stage II), and then slowed again before fusion with an endosome (stage III). The initial acidification step to ~pH 6 occurred after the rapid stage II movement in the perinuclear region. Previous studies have indicated that early endosomes are the site of initial acidification, but these results suggest that virus-containing endocytic compartments leave the early endosomes before this initial acidification.

    The Fujian strain of influenza A (H3N2) virus appears to be the currently predominant strain in the USA and Europe. The Panama strain, which is a constituent of the current vaccine, is responsible for the current outbreak in western Canada. Although there is believed to be sufficient antigenic cross-reactivity between the Fujian and Panama strains for the existing vaccine to be protective, it has been judged prudent to replace the Panama strain with the Fujian strain in the new Southern Hemisphere vaccine, although the Panama strain is still in circulation in some places.
    The mouse has been a valuable and extensively used model to study the mechanisms that protect against or promote recovery from this infection. Evidence indicates that components of both innateref1, ref2, ref3 and adaptiveref1, ref2 immune systems contribute to the control of the infection and that activities provided by CD4+ helper (Th) and B cellsref1, ref2 or CD8+ cytotoxic T (Tc) cellsref1, ref2, ref3 can independently resolve it, although the latter are generally believed to be more effective. The recovery process mediated by Th and B cells appears to depend largely on the generation of a Th-dependent antiviral Ab response, as neither Thref1, ref2, ref3 nor B cellsref are capable of resolving the infection on their own, while infection in SCID mice can be cured by treatment with Abs specific for the viral hemagglutinin (HA) moleculeref1, ref2. The high therapeutic efficacy of these Abs appears to be due to their ability to concomitantly suppress yield of progeny virus from infected cells and prevent released progeny virus to spread the infection to new host cellsref1, ref2. The Tc cell-mediated recovery process has been shown to rely mainly on the perforin/granzyme- and Fas-mediated killing of infected host cellsref1, ref2, while secretion of cytokines such as IFN-g, which may inhibit virus spread by inducing cellular resistance to infection, does not appear to play a significant roleref1, ref2, at least in the intact mouseref, but may become important if the Tc activity is being tested at its therapeutic thresholdref. The above implies that effector Tc (eTc) are capable of killing infected epithelial cells before the release of progeny virus. This is surprising in the case of an acute infection in which the eTc has available only a short window of time (between expression of viral peptides by MHC class I and release of virions) to perform this taskref1, ref2. The massive recruitment of virus-specific eTc into the cellular exudate of the infected airways at the time of virus clearance would be consistent with such a scenarioref. However, since evidence for the autonomy of Tc-mediated clearance was obtained in the study of influenza viruses of low pathogenicity, such as X31ref1, ref2 and B/AAref, we wondered whether eTc-mediated control mechanisms would be similarly effective also against a more pathogenic, and perhaps more rapidly replicating, influenza virus strain like PR8. There is evidence from other virus systems that rapidly replicating viruses such as vesicular stomatitis virus and Semliki Forest virus or more virulent variants of lymphocytic choriomeningitis virusare not effectively controlled by Tcref1, ref2, ref3, ref4, ref5. In addition, 2 of the influenza virus studiesref1, ref2 had been done in mice that contained B cells, although no Th cells. Therefore, the conclusion that Tc resolved the infection autonomously in these mice assumed that the B cells made no significant contribution to recovery without help from Th cells. B cell-deficient mice (µMT) of BALB/c background additionally depleted of Th cells by chronic treatment with anti-CD4 Ab GK1.5 were used to test the ability of the Tc response to autonomously resolve the highly pathogenic PR8 and the less pathogenic X31 virus infections : the study confirmed that the Tc response has the basic capability to autonomously (in conjunction with innate defense) resolve these infections, but with substantial delay compared with immunologically intact mice, which resulted in high mortality in infection with the pathogenic PR8 strain. The study further showed that B cells contributed to the recovery process by a Th-independent mechanism of still undefined natureref.
    However, in contrast to findings in mice, the protective value of memory Tc cells in humans remains controversial. The classic study by McMichael et al.ref indicated that presence of memory Tc cells in blood, which could give rise to Tc cells on stimulation in vitro, correlated with reduced virus shedding 3–4 days after volunteers were challenged with a wild-type virus, but had no significant effect on illness. Subsequent studies performed in children found no significant difference in shedding of attenuated vaccine strains in patients who had recovered from previous infection with a vaccine or natural strain of a different subtype than did study participants who had no evidence of previous virus exposureref (Wright PF, Johnson PR, Karzon DT. Clinical experience with live, attenuated vaccine in children. In: Options for the control of influenza;1986. New York: Alan R Liss, Inc. p. 243–53). Similarly, children vaccinated with an H1N1 strain showed no difference in attack rate and febrile respiratory illness during exposure to natural epidemic H3N2 virus from controls who received a placeboref

    The pathogenesis of influenza infections has been associated with alteration in the lymphohemopoietic systemref1, ref2, ref3, ref4, ref5,ref6, ref7 (20, 21, 29, 31, 50-52). Experimental infection of chickens with the avian influenza virus A/Turkey/Ontario/7732/66 (H5N9) (Ty/Ont) resulted in the destruction of lymphocytes and histopathological necrosis of lymphoid tissues. It was further demonstrated that the lymphocyte destruction in birds was associated with virus-induced apoptosis, as Ty/Ont, but not a human strain, A/Puerto Rico/8/34 (H1N1), induced apoptosis of an avian lymphocyte cell lineref. Whether an avian virus has an affinity for cells of the mammalian immune system, resulting in leukocyte death, remains an unanswered question. Infection of mice with a highly virulent H5N1 resulted in a decrease in peripheral blood and tissue lymphocytes and aberrant cytokine and chemokine production. An increase in apoptotic cells in the spleen and lung tissue is identified as a possible cause of lymphocyte death.

    A variety of influenza A viruses (avian, equine, swine, and human), as well as human influenza B viruses, induced DNA fragmentation in a permissive mammalian cell line, Madin-Darby canine kidney (MDCK), and this correlated with the development of a cytopathic effect during viral infection. Since the proto-oncogene bcl-2 is a known inhibitor of apoptosis, we transfected MDCK cells with the human bcl-2 gene; these stably transfected cells (MDCKbcl-2) did not undergo DNA fragmentation after virus infection. In addition, cytotoxicity assays at 48 to 72 h after virus infection showed a high level of cell viability for MDCKbcl-2 compared with a markedly lower level of viability for MDCK cells. These studies indicate that influenza A and B viruses induce apoptosis in cell cultures; thus, apoptosis may represent a general mechanism of cell death in hosts infected with influenza virusesref

    Influenza virus has been shown to induce apoptosis in tissue culture cellsref1, ref2 and in peripheral blood monocytesref1, ref2. A depletion of lymphocytes due to apoptosis has also been described in mice infected with a highly virulent influenza A virus (IAV) (H5N1) isolated from humansref. The immunopathological mechanisms and the role played by the virus infection of leukocytes with respect to disease pathology in general and leukocyte death in particular have not been elucidated. An early lymphopenia has been described in IAV-infected patientsref1, ref2, ref3, and inoculation of humans with IAV has been shown to cause a decrease in both T- and B-cell numbers during illnessref1, ref2. In the experimental infections, volunteers developed a severe T-cell lymphopenia and a moderate B-cell lymphopenia even though seroconversion occurred in 90% of the volunteers, suggesting that T- and B-cell functions were preservedref1, ref2. This observed lymphopenia could be the result of cell migration from the circulation and/or cell death caused by necrosis or by apoptosis or through suppression of hematopoeisis. Lymphocyte depletion via apoptosis after exposure to IAV could be the result of virus-induced cytokine stimulation, viral induction of Fas, or other cell-virus interactionsref.

    Among leukocytes, only monocytes and macrophages were found to be highly susceptible to an infection by influenza A virus. After infection, de novo viral protein synthesis was initiated but then interrupted after 4-6 h. Most macrophages died by apoptosis within 25-30 h. Before cell death, however, macrophages responded to influenza A virus with a high cytokine gene transcription and subsequent release of TNF-a, IL-1, IL-6, IFN-a/b, and CC-chemokines. The basic mechanisms of virus-induced cytokine expression are still unknown and appear to involve transcription factors such as NF-kB and AP-1 which, however, were only activated for 2 h and declined below control values thereafter. After influenza A virus infection, only the mononuclear cell attracting CC-chemokines MIP-1a, MIP-1b, and RANTES were produced while the prototype neutrophil CXC-chemoattractants IL-8 and GRO-a were entirely suppressed. This selective induction of CC-chemokines may explain the preferential influx of mononuclear leukocytes into virus-infected tissue. Monocytes and macrophages represent a primary target for an influenza A virus infection. Thus, the mononuclear phagocyte response leads to a rapid proinflammatory reaction and an enhanced immigration of mononuclear leukocytes, which may condition the infected host for the subsequent virus antigen-specific defenseref

    During acute illnessref or induced infectionref, lymphopenia is evident as reduced numbers of B and T cells. This may reflect migration of lymphocytes to the site of infection, and it would therefore be reasonable to expect that lymphopenia would correlate with recovery from infection. However, in the recent influenza A virus H5N1 outbreak, low leukocyte counts correlated with severity of diseaseref. In addition, the T cells present during acute infection are functionally impaired, with reduced lectin-induced stimulationref1, ref2, suggesting that these quantitative and qualitative changes may not simply be due to migration of cells. A number of factors probably contribute to these observations. For example, virus load, as well as viral components that confer pathogenicity, may influence the milieu of cytokines and the composition of responding cells. These factors may act on both naïve and effector B and T cells to result in lymphopenia. The cell type that may mediate this lack of response is the dendritic cell (DC), since it transports virus to the draining lymph noderef and has direct contact with T cells. The interactions between DC and naïve and memory T cells determine both the magnitude and quality of the immune response. Influenza virus alters this interaction in vitroref. In this in vitro system, we examined the effects of influenza virus infection on DC function. DC were cultured from H-2b bone marrow and then used to stimulate H-2d allogeneic T cells. Since this response is not virus specific, the ramifications of influenza virus infection were determined by comparing T-cell proliferation stimulated by uninfected and virus-infected DC. When DC were infected with a low dose of A/PR/8/34 (PR8), there was increased T-cell proliferation in response to influenza virus-infected DCref. This altered response was dependent on viral neuraminidase (NA) and did not require infection of the DC with influenza virus. One or more mechanisms may mediate this effect when sialic acid is removed from glycoconjugates at the DC surface. This may include changes that facilitate interactions between the major histocompatibility complex (MHC) class I-peptide complex with the TcR, B7-1 with CD28, and adhesins with their ligands or changes in charge at the cell's surface that result in a general increase in contact. However, our current results show that this enhanced proliferative response is not observed when DC are infected with high doses of PR8. There may be multiple reasons for the lack of an enhanced response at high PR8 multiplicity of infection (MOI). For example, since influenza virus induces apoptosis of infected cellsref, greater numbers of virus particles may induce greater DC apoptosis, thereby reducing the number of effective stimulators in the culture. Alternatively, at high doses of virus, virions released from the DC may interact with T cells, resulting in their reduced proliferation. Viral NA could contribute to this reduced response by desialylation of T-cell surface glycoproteins. This would result in DC and T cells having equal charges, so that opposite attractive charges would no longer facilitate the interaction between them. Other reasons for the dose-dependent proliferative response may be that properties of DC that contribute to successful T-cell activation are altered at high virus doses, or that, under these conditions, cytokines that inhibit proliferation are secreted. At a high MOI, a number of changes occur in DC. The most notable physical change that provides a reasonable mechanism to explain the reduced response to DC infected with high doses of PR8 is the formation of DC clusters that exclude T cells. However, neutralization of TGF-b1 restored the enhanced alloreactive T-cell response, suggesting that this cytokine plays a primary role in reducing proliferationref.

    Laboratory examinations : => epidemic flu or influenza / grip [Fr. grippe] after 1-3 days incubation : fever, dry cough, profound sinus tachycardia, myoarthralgia, anorexia, photophobia, acute rhinitis. Self-limiting within 3-5 days.
    Therapy : Prevention : Complications : pregnant women are at higher risk than nonpregnant women for having complications secondary to influenza. Pregnant women who will be in their 2nd or 3rd trimester during influenza season should be vaccinated against influenza
    Prognosis : see above
    Web resources :

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