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• W1968895930 abstract "Both seasonal and pandemic influenza continue to challenge both scientists and clinicians. Drug-resistant H1N1 influenza viruses have dominated the 2009 flu season, and the H5N1 avian influenza virus continues to kill both people and poultry in Eurasia. Here, we discuss the pathogenesis and transmissibility of influenza viruses and we emphasize the need to find better predictors of both seasonal and potentially pandemic influenza. Both seasonal and pandemic influenza continue to challenge both scientists and clinicians. Drug-resistant H1N1 influenza viruses have dominated the 2009 flu season, and the H5N1 avian influenza virus continues to kill both people and poultry in Eurasia. Here, we discuss the pathogenesis and transmissibility of influenza viruses and we emphasize the need to find better predictors of both seasonal and potentially pandemic influenza. Influenza is historically an ancient disease that causes annual epidemics and, at irregular intervals, pandemics. Seasonal influenza kills 36,000 persons annually in the United States. The impact of seasonal influenza caused by a virus showing antigenic variation in the major viral glycoproteins hemagglutinin (H) and neuraminidase (N) can be moderated by antigenically matched vaccines and anti-influenza drugs. The consequences of continuing genetic variation in seasonal influenza viruses are apparent in the current and prior influenza seasons. Despite intensive global surveillance, the H3N2 vaccine in the 2007–2008 season imperfectly matched the virus that emerged between vaccine selection and its use (6 months). In the current influenza season, the H1N1 virus that has become dominant is resistant to the anti-influenza drug oseltamivir (Tamiflu). Pandemics that occur at irregular intervals can vary in severity from mild to catastrophic. The pandemics of the past century include the catastrophic H1N1 Spanish influenza of 1918 (more than 50 million deaths globally), the H2N2 Asian flu of 1957 (more than 1 million deaths globally), and the H3N2 Hong Kong flu of 1968 (∼0.5 million deaths globally). The natural reservoirs of these influenza A viruses are aquatic birds, and the spread of influenza to humans occurs either by direct transmission (Spanish influenza) or by reassortment between the segmented RNA genomes of avian and human influenza viruses (the Asian and Hong Kong pandemics). Although we know the general mechanisms by which new influenza viruses emerge, our basic knowledge of how these viruses acquire human pandemic potential is minimal, and our molecular understanding of the virus and the host factors involved in successful transmission and spread is rudimentary. A highly pathogenic H5N1 avian influenza virus has been circulating for more than a decade in Eurasia and has spread to more than 60 countries. It has infected 394 humans killing 248, with recent deaths reported in China, Indonesia, Vietnam, and Egypt. The occasional direct transmission of the virus to humans and its lethality suggest the possibility of a pandemic akin to the 1918 Spanish flu if consistent human-to-human transmission is achieved. We argue that it is premature to become complacent, and we identify research directions in influenza virus ecology and the molecular biology of pathogenesis and transmission that should enable the development of better predictors of seasonal and pandemic influenza and increased preparedness (Figure 1). The 16 hemagglutinin and 9 neuraminidase subtypes of influenza A virus are perpetuated in aquatic birds, in which they cause no apparent disease (Peiris et al., 2007Peiris J.S. de Jong M.D. Guan Y. Avian influenza virus (H5N1): a threat to human health.Clin. Microbiol. Rev. 2007; 20: 243-267Crossref PubMed Scopus (702) Google Scholar). Only viruses of the H5 and H7 hemagglutinin subtypes can become highly pathogenic after transmission to alternative hosts. Each of the H5 and H7 lineages that are lethal to domestic poultry originated from nonpathogenic precursor viruses of Eurasian and American lineages (Alexander, 2007Alexander D.J. An overview of the epidemiology of avian influenza.Vaccine. 2007; 25: 5637-5644Crossref PubMed Scopus (611) Google Scholar). However, until 1996, highly pathogenic H5 and H7 viruses either were eradicated or failed to persist in nature. Today, it is unknown whether the ecology of these viruses has changed and whether highly pathogenic H5N1 viruses continue to be propagated in domestic or wild bird reservoirs. The continued circulation of Asian H5N1 viruses of multiple clades (at least 10 different clades) and subclades is unprecedented. The available evidence suggests that all of the pandemic influenza virus strains, including the Spanish 1918 (H1N1), Asian 1957 (H2N2), and Hong Kong 1968 (H3N2) viruses, originated from the avian influenza reservoir either by reassortment (swapping of viral genetic information in hosts coinfected with more than one influenza virus) or direct transfer (Kobasa et al., 2004Kobasa D. Takada A. Shinya K. Hatta M. Halfmann P. Theriault S. Suzuki H. Nishimura H. Mitamura K. Sugaya N. et al.Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.Nature. 2004; 431: 703-707Crossref PubMed Scopus (396) Google Scholar). Influenza outbreaks in domestic animals, including poultry, also originate from the avian reservoir. Our knowledge of the precursors of pandemic and panzootic influenza viruses is extremely limited. The available information indicates that viruses in their natural reservoirs undergo limited evolution, replicate primarily in the intestinal and respiratory tracts, and change their predominant subtypes every 2 years (Fouchier et al., 2003Fouchier R.A. Osterhaus A.D. Brown I.H. Animal influenza virus surveillance.Vaccine. 2003; 21: 1754-1757Crossref PubMed Scopus (50) Google Scholar). Knowledge of the genomics of influenza viruses in this natural reservoir is fragmentary, and evidence suggests that there is continuing reassortment in nature (Dugan et al., 2008Dugan V.G. Chen R. Spiro D.J. Sengamalay N. Zaborsky J. Ghedin E. Nolting J. Swayne D.E. Runstadler J.A. Happ G.M. et al.The evolutionary genetics and emergence of avian influenza viruses in wild birds.PLoS Pathog. 2008; 4: e1000076https://doi.org/10.1371/journal.ppat.1000076Crossref PubMed Scopus (307) Google Scholar, Obenauer et al., 2006Obenauer J.C. Denson J. Mehta P.K. Su X. Mukatira S. Finkelstein D.B. Xu X. Wang J. Ma J. Fan Y. et al.Large-scale sequence analysis of avian influenza isolates.Science. 2006; 311: 1576-1580Crossref PubMed Scopus (490) Google Scholar). Analysis of the multiple lineages of highly pathogenic H5N1 viruses supports the contention that all of them arose in Southeast Asia (Kilpatrick et al., 2006Kilpatrick A.M. Chmura A.A. Gibbons D.W. Fleischer R.C. Marra P.P. Daszak P. Predicting the global spread of H5N1 avian influenza.Proc. Natl. Acad. Sci. USA. 2006; 103: 19368-19373Crossref PubMed Scopus (435) Google Scholar, Smith et al., 2006Smith G.J. Fan X.H. Wang J. Li K.S. Qin K. Zhang J.X. Vijaykrishna D. Cheung C.L. Huang K. Rayner J.M. et al.Emergence and predominance of an H5N1 influenza variant in China.Proc. Natl. Acad. Sci. USA. 2006; 103: 16936-16941Crossref PubMed Scopus (275) Google Scholar). For example, the H5N1 virus that emerged at Qinghai Lake, China spread (probably in wild birds) to Europe, Africa, and India (Li et al., 2004Li K.S. Guan Y. Wang J. Smith G.J. Xu K.M. Duan L. Rahardjo A.P. Puthavathana P. Buranathai C. Nguyen T.D. et al.Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia.Nature. 2004; 430: 209-213Crossref PubMed Scopus (1105) Google Scholar). Similarly, the lineage that spread to Indonesia can be traced to China's Hunan Province (Wang et al., 2008Wang J. Vijaykrishna D. Duan L. Bahl J. Zhang J.X. Webster R.G. Peiris J.S. Chen H. Smith G.J. Guan Y. Identification of the progenitors of Indonesia and Vietnam avian influenza A (H5N1) viruses from southern China.J. Virol. 2008; 82: 3405-3414Crossref PubMed Scopus (83) Google Scholar). The domestic duck may be the “Trojan horse” of the H5N1 viruses, for many ducks show no signs of disease yet shed virus for up to 17 days after infection and propagate influenza virus antigenic variants with low pathogenicity (Hulse et al., 2005Hulse D.J. Sturm-Ramirez K.M. Humbred J. Seiler P. Govorkova E.A. Krauss S. Scholtissek C. Puthavathana P. Buranathai C. Nguyen T.D. et al.Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia.Proc. Natl. Acad. Sci. USA. 2005; 102: 10682-10687Crossref PubMed Scopus (411) Google Scholar). This hypothesis will be resolved only by detailed molecular epidemiological studies. To date, there is no influenza surveillance system in lower animals and birds that is comparable to the well-organized, interactive Global Influenza Surveillance Network (GISN) for human influenza. The pandemic threat of H5N1 influenza has resulted in closer collaborations between international agricultural and human health organizations. However, the lack of a counterpart of GISN at the human-animal interface is a serious shortfall in pandemic preparedness. A genomic library of all subtypes of influenza viruses in wild and domestic birds, continuously updated by high-throughput sequencing and analysis, is badly needed to identify predictors of pandemics. Influenza viruses probably undergo genetic changes to spread from the wild bird reservoir to other hosts. Such changes are facilitated when multiple species of birds and mammals are housed in close proximity in live animal markets (Webster, 2004Webster R.G. Wet markets–a continuing source of severe acute respiratory syndrome and influenza?.Lancet. 2004; 363: 234-236Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). It is unclear whether influenza viruses are transmitted directly from natural reservoirs to mammals, including humans. Notably, chickens are not susceptible to most of the low-pathogenicity subtypes, including nonpathogenic H5 and H7 strains, without adaptation (Swayne, 2007Swayne D.E. Understanding the complex pathobiology of high pathogenicity avian influenza viruses in birds.Avian Dis. 2007; 51: 242-249Crossref PubMed Google Scholar). The involvement of intermediate hosts, including the quail and the pig, has been suggested (Matrosovich et al., 1999Matrosovich M. Zhou N. Kawaoka Y. Webster R. The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties.J. Virol. 1999; 73: 1146-1155PubMed Google Scholar), but there is no smoking gun. A suggested transmission scenario might follow this sequence: wild waterfowl → domestic waterfowl → quail/pig → chicken → human. All of these birds and some mammals are found in various live markets. Information about the molecular profiles that permit transmission between these species is emerging (Perez et al., 2003Perez D.R. Lim W. Seiler J.P. Yi G. Peiris M. Shortridge K.F. Webster R.G. Role of quail in the interspecies transmission of H9 influenza A viruses: molecular changes on HA that correspond to adaptation from ducks to chickens.J. Virol. 2003; 77: 3148-3156Crossref PubMed Scopus (174) Google Scholar), but there is much still to learn. Expansion of the host range of the Asian H5N1 avian influenza virus to felines, viverrids, stone martens, and dogs has been associated with high pathogenicity and systemic spread (Rimmelzwaan et al., 2006Rimmelzwaan G.F. van Riel D. Baars M. Bestebroer T.M. van Amerongen G. Fouchier R.A. Osterhaus A.D. Kuiken T. Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts.Am. J. Pathol. 2006; 168: 176-183Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, Songserm et al., 2006Songserm T. Amonsin A. Jam-on R. Sae-Heng N. Pariyothorn N. Payungporn S. Theamboonlers A. Chutinimitkul S. Thanawongnuwech R. Poovorawan Y. Fatal avian influenza A H5N1 in a dog.Emerg. Infect. Dis. 2006; 12: 1744-1747Crossref PubMed Scopus (214) Google Scholar). Extension of the host range to felid species remains to be elucidated at the molecular level; if domestic cats can serve as intermediate hosts, their infection would promote the selection of variants transmissible to humans. The pig may be an intermediate host for interspecies spread; the replication of all avian viruses in pigs supports this notion, as does the presence of avian-type and mammalian-type virus receptors in pigs (Ludwig et al., 1995Ludwig S. Stitz L. Planz O. Van H. Fitch W.M. Scholtissek C. European swine virus as a possible source for the next influenza pandemic?.Virology. 1995; 212: 555-561Crossref PubMed Scopus (99) Google Scholar). The periodic transmission of avian influenza viruses to pigs in the absence of disease and the spread of human H1N1 and H3N2 viruses to pigs (Ma et al., 2007Ma W. Vincent A.L. Gramer M.R. Brockwell C.B. Lager K.M. Janke B.H. Gauger P.C. Patnayak D.P. Webby R.J. Richt J.A. Identification of H2N3 influenza A viruses from swine in the United States.Proc. Natl. Acad. Sci. USA. 2007; 104: 20949-20954Crossref PubMed Scopus (181) Google Scholar) are also consistent with the “mixing-vessel” hypothesis, but to date the pig has not been directly implicated in the generation of pandemic influenza viruses. A major enigma of influenza virus is whether alteration of viral specificity for host cell receptors (sialic acids) can generate a pandemic strain of virus. The viral hemagglutinin surface glycoprotein preferentially binds to certain sialic acid residues on host cells, making hemagglutinin a determinant of host range. Specific amino acid changes in hemagglutinin have been identified as important in sialic acid receptor specificity and pathogenicity (Matrosovich et al., 1999Matrosovich M. Zhou N. Kawaoka Y. Webster R. The surface glycoproteins of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties.J. Virol. 1999; 73: 1146-1155PubMed Google Scholar, Stevens et al., 2006bStevens J. Blixt O. Tumpey T.M. Taubenberger J.K. Paulson J.C. Wilson I.A. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus.Science. 2006; 312: 404-410Crossref PubMed Scopus (797) Google Scholar, Yamada et al., 2006Yamada S. Suzuki Y. Suzuki T. Le M.Q. Nidom C.A. Sakai-Tagawa Y. Muramoto Y. Ito M. Kiso M. Horimoto T. et al.Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors.Nature. 2006; 444: 378-382Crossref PubMed Scopus (504) Google Scholar). The hemagglutinin of human influenza virus isolates typically binds preferentially to α2,6-linked sialic acids, whereas that of avian influenza virus isolates has a higher affinity for α2,3-linked sialic acids (Ito, 2000Ito T. Interspecies transmission and receptor recognition of influenza A viruses.Microbiol. Immunol. 2000; 44: 423-430Crossref PubMed Scopus (73) Google Scholar). Interestingly, sialic acid receptors are distributed differently in the respiratory tracts of humans and other host species (Matrosovich et al., 2004Matrosovich M.N. Matrosovich T.Y. Gray T. Roberts N.A. Klenk H.D. Human and avian influenza viruses target different cell types in cultures of human airway epithelium.Proc. Natl. Acad. Sci. USA. 2004; 101: 4620-4624Crossref PubMed Scopus (608) Google Scholar, Shinya et al., 2006Shinya K. Ebina M. Yamada S. Ono M. Kasai N. Kawaoka Y. Avian flu: influenza virus receptors in the human airway.Nature. 2006; 440: 435-436Crossref PubMed Scopus (1090) Google Scholar, van Riel et al., 2007van Riel D. Munster V.J. de Wit E. Rimmelzwaan G.F. Fouchier R.A. Osterhaus A.D. Kuiken T. Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals.Am. J. Pathol. 2007; 171: 1215-1223Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar). The human and ferret upper respiratory tract, believed to be the primary site of influenza infection, carries primarily α2,6-linked sialic acids, which gives human viral isolates a binding advantage. Receptor specificity must be studied at the level of the cell type to discern the relative susceptibility of cells to infection on the basis of sialic acid expression. This information will be of particular interest, as some H5N1 viruses cause systemic infection, including infection of brain cells. Notably, the 1918, 1957, and 1968 pandemic strains all preferentially bind to α2,6-linked sialic acids (Stevens et al., 2006aStevens J. Blixt O. Glaser L. Taubenberger J.K. Palese P. Paulson J.C. Wilson I.A. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities.J. Mol. Biol. 2006; 355: 1143-1155Crossref PubMed Scopus (536) Google Scholar), and so preferential affinity for these receptors may be necessary for emergence of a pandemic strain carrying an avian-derived hemagglutinin gene. However, avian isolates that bind preferentially to α2,3-linked sialic acids are lethal in humans and mammals and replicate well in the upper respiratory tract. Thus, it remains an open question whether H5N1 viruses must acquire specificity for binding to α2,6-linked sialic acids to become pandemic. Interestingly, cultured human respiratory epithelial cells lacking α2,3-linked sialic acids could be infected ex vivo with H5N1 viruses (Nicholls et al., 2007Nicholls J.M. Chan M.C. Chan W.Y. Wong H.K. Cheung C.Y. Kwong D.L. Wong M.P. Chui W.H. Poon L.L. Tsao S.W. et al.Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract.Nat. Med. 2007; 13: 147-149Crossref PubMed Scopus (281) Google Scholar). This finding together with advances in glycan array technology (Stevens et al., 2006aStevens J. Blixt O. Glaser L. Taubenberger J.K. Palese P. Paulson J.C. Wilson I.A. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities.J. Mol. Biol. 2006; 355: 1143-1155Crossref PubMed Scopus (536) Google Scholar) suggest that receptor specificity may involve factors other than binding to α2,3-linked and α2,6-linked sialic acids. However, the biological relevance of receptor binding particularly for viral entry, replication, spread, tissue tropism, and transmission still needs to be determined. What other viral factors increase the virulence or transmission of influenza virus, and by what mechanism? Certain H5N1 viruses with a hemagglutinin that preferentially binds to α2,3-linked sialic acids replicate in humans and can be lethal, suggesting that genes other than that encoding hemagglutinin are crucial for virulence. The replication efficiency of influenza virus correlates with its virulence. Specific amino acid sequences encoded by the polymerase genes alone are sufficient to make a virus lethal in animal models (Gabriel et al., 2005Gabriel G. Dauber B. Wolff T. Planz O. Klenk H.D. Stech J. The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host.Proc. Natl. Acad. Sci. USA. 2005; 102: 18590-18595Crossref PubMed Scopus (548) Google Scholar, Hatta et al., 2001Hatta M. Gao P. Halfmann P. Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.Science. 2001; 293: 1840-1842Crossref PubMed Scopus (1123) Google Scholar, Salomon et al., 2006Salomon R. Franks J. Govorkova E.A. Ilyushina N.A. Yen H.L. Hulse-Post D.J. Humberd J. Trichet M. Rehg J.E. Webby R.J. et al.The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04.J. Exp. Med. 2006; 203: 689-697Crossref PubMed Scopus (306) Google Scholar). The best-described marker of pathogenicity is lysine at position 627 of polymerase subunit protein PB2 (Hatta et al., 2001Hatta M. Gao P. Halfmann P. Kawaoka Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.Science. 2001; 293: 1840-1842Crossref PubMed Scopus (1123) Google Scholar, Subbarao et al., 1993Subbarao E.K. London W. Murphy B.R. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range.J. Virol. 1993; 67: 1761-1764Crossref PubMed Google Scholar). This residue enhances the growth efficiency of avian H5N1 viruses in the upper and lower respiratory tracts of mice. As the importance of specific polymerase residues to lethality is identified, it will be crucial to elucidate the mechanism by which these residues affect replication efficiency. Each of the eight negative-sense RNA segments of influenza virus is transcribed into mRNA by the viral ribonucleoprotein (RNP) complex comprised of the PB2, PB1, PA, and NP proteins (Figure 2). Crystal structures of portions of the RNP complex have already shed light on how these proteins work (He et al., 2008He X. Zhou J. Bartlam M. Zhang R. Ma J. Lou Z. Li X. Li J. Joachimiak A. Zeng Z. et al.Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus.Nature. 2008; 454: 1123-1126Crossref PubMed Scopus (247) Google Scholar, Noda et al., 2006Noda T. Sagara H. Yen A. Takada A. Kida H. Cheng R.H. Kawaoka Y. Architecture of ribonucleoprotein complexes in influenza A virus particles.Nature. 2006; 439: 490-492Crossref PubMed Scopus (316) Google Scholar). However, more biochemical research into the structure of the complex is needed to reveal why certain residues affect the interaction of the polymerase proteins, viral RNA, and host proteins. Elucidating how receptor specificity and polymerase-driven replication affect the pathogenicity and transmission of H5N1 viruses will yield important clues about host adaptation, pandemic potential, and the development of antiviral drugs. What are the requirements for human-to-human transmission of a potentially pandemic highly pathogenic avian influenza virus, and what mechanisms are involved? The absence of efficient human-to-human transmission of H5N1 viruses to date may explain why the circulating avian influenza virus has not caused a pandemic. Ferrets, which are naturally susceptible to influenza, have been used as a model to investigate transmission of H5N1 viruses. In both humans and ferrets, respiratory epithelial cells express primarily α2,6-linked sialic acids, H5N1 viruses bind preferentially to epithelial cells in the lower respiratory tract, and infection causes acute respiratory illness (Matrosovich et al., 2004Matrosovich M.N. Matrosovich T.Y. Gray T. Roberts N.A. Klenk H.D. Human and avian influenza viruses target different cell types in cultures of human airway epithelium.Proc. Natl. Acad. Sci. USA. 2004; 101: 4620-4624Crossref PubMed Scopus (608) Google Scholar, Shinya et al., 2006Shinya K. Ebina M. Yamada S. Ono M. Kasai N. Kawaoka Y. Avian flu: influenza virus receptors in the human airway.Nature. 2006; 440: 435-436Crossref PubMed Scopus (1090) Google Scholar, van Riel et al., 2007van Riel D. Munster V.J. de Wit E. Rimmelzwaan G.F. Fouchier R.A. Osterhaus A.D. Kuiken T. Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals.Am. J. Pathol. 2007; 171: 1215-1223Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar). Pathogenic H5N1 virus was not transmitted from infected to contact ferrets regardless of the α2,3- or α2,6-linked sialic acid receptor binding affinity (Yen et al., 2007bYen H.L. Lipatov A.S. Ilyushina N.A. Govorkova E.A. Franks J. Yilmaz N. Douglas A. Hay A. Krauss S. Rehg J.E. et al.Inefficient transmission of H5N1 influenza viruses in a ferret contact model.J. Virol. 2007; 81: 6890-6898Crossref PubMed Scopus (128) Google Scholar). In another study, acquisition of the surface glycoproteins of efficiently transmissible H3N2 human influenza viruses did not alter transmission of poorly transmissible H5N1 avian viruses (Maines et al., 2006Maines T.R. Chen L.M. Matsuoka Y. Chen H. Rowe T. Ortin J. Falcon A. Nguyen T.H. Mai le Q. Sedyaningsih E.R. et al.Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model.Proc. Natl. Acad. Sci. USA. 2006; 103: 12121-12126Crossref PubMed Scopus (296) Google Scholar), suggesting that H5N1 transmission involves multiple genetic adaptations. Factors beyond the viral genome may also contribute to transmissibility. For example, virus is thought to be transmitted in droplets generated by coughing or sneezing. In a guinea pig model of human infection, H3N2 influenza virus was indeed transmitted via an aerosol, and aerosol transmission was enhanced by lower humidity and temperature (Lowen et al., 2007Lowen A.C. Mubareka S. Steel J. Palese P. Influenza virus transmission is dependent on relative humidity and temperature.PLoS Pathog. 2007; 3: e151https://doi.org/10.1371/journal.ppat.0030151Crossref Scopus (1065) Google Scholar). These findings shed light on the seasonality of human influenza outbreaks. Importantly, however, H3N2 influenza virus is transmitted among guinea pigs without coughing and sneezing, which is not true in ferrets. If H5N1 viruses do acquire efficient human-to-human transmissibility, it will be important to understand the full range of factors that can modulate transmission. The coinfection of a human by a seasonal H3N2 influenza virus with efficient transmissibility and an avian H5N1 virus with poor transmissibility has the potential to generate a reassortant H5N1 virus with efficient transmission or pandemic potential. In a hallmark study, the reassortant viruses generated from swapping the genes of H5N1 and H3N2 influenza viruses did not yield influenza viruses with efficient transmissibility in ferrets (Maines et al., 2006Maines T.R. Chen L.M. Matsuoka Y. Chen H. Rowe T. Ortin J. Falcon A. Nguyen T.H. Mai le Q. Sedyaningsih E.R. et al.Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model.Proc. Natl. Acad. Sci. USA. 2006; 103: 12121-12126Crossref PubMed Scopus (296) Google Scholar). Nevertheless, there is still concern about coinfection of humans and the emergence of H5N1 viruses with efficient human-to-human transmission. Multiple different genotypes of avian H5N1 viruses continue to emerge and the possibility of coinfection of humans with both avian H5N1 and seasonal H1N1 or H3N2 influenza virus is a continuing possibility. The possibility of genetic reassortment between these influenza viruses resulting in an H5N1 virus with increased ability to transmit between humans indicates that increased surveillance is needed to capture these coinfections of H5N1 and other influenza viruses and to elucidate which genetic reassortments will result in an influenza virus with pandemic potential. The contribution to pathogenesis of coinfections with influenza virus and bacteria is another intriguing research area. Evidence suggests that a majority of deaths during the 1918 Spanish flu pandemic were due to secondary bacterial pneumonia (McCullers, 2006McCullers J.A. Insights into the interaction between influenza virus and pneumococcus.Clin. Microbiol. Rev. 2006; 19: 571-582Crossref PubMed Scopus (639) Google Scholar, Morens et al., 2008Morens D.M. Taubenberger J.K. Fauci A.S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.J. Infect. Dis. 2008; 198: 962-970Crossref PubMed Scopus (1124) Google Scholar). Major knowledge gaps exist in our understanding of the complex interactions of multiple pathogens with each other and with the coinfected host. Thus, research and pandemic preparedness will require a focus on secondary bacterial infection and treatment. The pathology induced by some strains of influenza A virus has been correlated with an excessive immune response (de Jong et al., 2006de Jong M.D. Simmons C.P. Thanh T.T. Hien V.M. Smith G.J. Chau T.N. Hoang D.M. Chau N.V. Khanh T.H. Dong V.C. et al.Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.Nat. Med. 2006; 12: 1203-1207Crossref PubMed Scopus (1501) Google Scholar). Studies of innate immune cells (dendritic cells, monocytes, natural killer cells, and neutrophils) and of the CD4, CD8, and B lymphocytes during infection with H5N1 avian influenza virus are necessary to understand the protective and pathologic effects of the adaptive immune response and to inform the design of vaccines. The fundamental questions are the tissues in which these immune cells act, the effector functions they perform, and the requirements and mechanisms that regulate these functions. The rapid accumulation of proinflammatory cytokines (“cytokine storm”) after infection, with either the currently circulating highly pathogenic avian influenza virus or the 1918 Spanish influenza virus, is thought to play a prominent role in morbidity and mortality (Cheung et al., 2002Cheung C.Y. Poon L.L. Lau A.S. Luk W. Lau Y.L. Shortridge K.F. Gordon S. Guan Y. Peiris J.S. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?.Lancet. 2002; 360: 1831-1837Abstract Full Text Full Text PDF PubMed Scopus (735) Google Scholar, de Jong et al., 2006de Jong M.D. Simmons C.P. Thanh T.T. Hien V.M. Smith G.J. Chau T.N. Hoang D.M. Chau N.V. Khanh T.H. Dong V.C. et al.Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.Nat. Med. 2006; 12: 1203-1207Crossref PubMed Scopus (1501) Google Scholar, Kash et al., 2006bKash J.C. Tumpey T.M. Proll S.C. Carter V. Perwitasari O. Thomas M.J. Basler C.F. Palese P. Taubenberger J.K. Garcia-Sastre A. et al.Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus.Nature. 2006; 443: 578-581Crossref PubMed Scopus (466) Google Scholar). Levels of mRNAs" @default.
• W1968895930 created "2016-06-24" @default.
• W1968895930 creator A5002368359 @default.
• W1968895930 creator A5091454011 @default.
• W1968895930 date "2009-02-01" @default.
• W1968895930 modified "2023-10-14" @default.
• W1968895930 title "The Influenza Virus Enigma" @default.
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