Influenza virus: The biology of a changing virus

  • Samira Mubareka
  • Peter Palese
Part of the Birkhäuser Advances in Infectious Diseases book series (BAID)


Recent discoveries in the field of influenza virology are the focus of this chapter. Influenza viruses are members of the family Orthomyxoviridae and include influenza virus types A, B, and C. This introduction provides a detailed overview of influenza virus classification, structure, and life cycle. We also include a brief review of the clinical manifestations of influenza and the molecular determinants for virulence. The genetic diversity of influenza A viruses and their capability to successfully infect an array of hosts, including avian and mammalian species, is highlighted in a discussion about host range and evolution. The importance of viral receptor-binding hemagglutinins and host sialic acid distribution in species-restricted binding of viruses is underscored. Finally, recent advances in our understanding of the seasonality and transmission of influenza viruses are described and their importance for the control of the spread of these viruses discussed.


Influenza Virus Avian Influenza Virus Human Influenza Virus Sialic Acid Receptor Change Virus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Shaw ML, Palese P (2007) Orthomyxoviridae: The viruses and their replication. In: DM Knipe, PM Howley (eds): Fields Virology, 5th edn. Lippincott Williams & Wilkins, Philadelpha, 1647–1689Google Scholar
  2. 2.
    Fodor E, Devenish L, Engelhardt OG, Palese P, Brownlee GG, Garcia-Sastre A (1999) Rescue of influenza A virus from recombinant DNA. J Virol 73: 9679–9682PubMedGoogle Scholar
  3. 3.
    Neumann G, Watanabe T, Ito H, Watanabe S, Goto H, Gao P, Hughes M, Perez DR, Donis R, Hoffmann E et al (1999) Generation of influenza A viruses entirely from cloned cDNAs. Proc Natl Acad Sci USA 96: 9345–9350PubMedGoogle Scholar
  4. 4.
    Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, Garcia-Sastre A (2005) Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310: 77–80PubMedGoogle Scholar
  5. 5.
    World Health Organization Global Influenza Program Surveillance Network (2005) Evolution of H5N1 avian influenza viruses in Asia. Emerg Infect Dis 11: 1515–1521Google Scholar
  6. 6.
    Ghedin E, Sengamalay NA, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro DJ, Sitz J, Koo H, Bolotov P et al (2005) Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature 437: 1162–1166PubMedGoogle Scholar
  7. 7.
    Studahl M (2003) Influenza virus and CNS manifestations. J Clin Virol 28: 225–232PubMedGoogle Scholar
  8. 8.
    Sion ML, Hatzitolios AI, Toulis EN, Mikoudi KD, Ziakas GN (2001) Toxic shock syndrome complicating influenza A infection: A two-case report with one case of bacteremia and endocarditis. Intensive Care Med 27: 443PubMedGoogle Scholar
  9. 9.
    Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA (2000) Influenza B virus in seals. Science 288: 1051–1053PubMedGoogle Scholar
  10. 10.
    Newland JG, Romero JR, Varman M, Drake C, Holst A, Safranek T, Subbarao K (2003) Encephalitis associated with influenza B virus infection in 2 children and a review of the literature. Clin Infect Dis 36: e87–95Google Scholar
  11. 11.
    Jaimovich DG, Kumar A, Shabino CL, Formoli R (1992) Influenza B virus infection associated with non-bacterial septic shock-like illness. J Infect 25: 311–315PubMedGoogle Scholar
  12. 12.
    Chen JM, Guo YJ, Wu KY, Guo JF, Wang M, Dong J, Zhang Y, Li Z, Shu YL (2007) Exploration of the emergence of the Victoria lineage of influenza B virus. Arch Virol 152: 415–422PubMedGoogle Scholar
  13. 13.
    Hite LK, Glezen WP, Demmler GJ, Munoz FM (2007) Medically attended pediatric influenza during the resurgence of the Victoria lineage of influenza B virus. Int J Infect Dis 11: 40–47PubMedGoogle Scholar
  14. 14.
    Matsuzaki Y, Abiko C, Mizuta K, Sugawara K, Takashita E, Muraki Y, Suzuki H, Mikawa M, Shimada S, Sato K et al (2007) A nationwide epidemic of influenza C virus infection in Japan in 2004. J Clin Microbiol 45: 783–788PubMedGoogle Scholar
  15. 15.
    Yuanji G, Desselberger U (1984) Genome analysis of influenza C viruses isolated in 1981/82 from pigs in China. J Gen Virol 65: 1857–1872PubMedGoogle Scholar
  16. 16.
    Wright PF, Neumann G, Kawaoka Y (2007) Orthomyxoviruses. In: DM Knipe, PM Howley (eds): Fields Virology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, 1714–1715Google Scholar
  17. 17.
    Eisen MB, Sabesan S, Skehel JJ, Wiley DC (1997) Binding of the influenza A virus to cell-surface receptors: Structures of five hemagglutinin-sialyloligosaccharide complexes determined by X-ray crystallography. Virology 232: 19–31PubMedGoogle Scholar
  18. 18.
    Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: The influenza hemagglutinin. Annu Rev Biochem 69: 531–569PubMedGoogle Scholar
  19. 19.
    Glaser L, Stevens J, Zamarin D, Wilson IA, Garcia-Sastre A, Tumpey TM, Basler CF, Taubenberger JK, Palese P (2005) A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol 79: 11533–11536PubMedGoogle Scholar
  20. 20.
    Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson IA (2004) Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303: 1866–1870PubMedGoogle Scholar
  21. 21.
    Sieczkarski SB, Whittaker GR (2005) Viral entry. Curr Top Microbiol Immunol 285: 1–23PubMedGoogle Scholar
  22. 22.
    Matlin KS, Reggio H, Helenius A, Simons K (1981) Infectious entry pathway of influenza virus in a canine kidney cell line. J Cell Biol 91: 601–613PubMedGoogle Scholar
  23. 23.
    Nunes-Correia I, Eulalio A, Nir S, Pedroso de Lima MC (2004) Caveolae as an additional route for influenza virus endocytosis in MDCK cells. Cell Mol Biol Lett 9: 47–60PubMedGoogle Scholar
  24. 24.
    Takeda M, Pekosz A, Shuck K, Pinto LH, Lamb RA (2002) Influenza A virus M2 ion channel activity is essential for efficient replication in tissue culture. J Virol 76: 1391–1399PubMedGoogle Scholar
  25. 25.
    Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel activity. Cell 69: 517–528PubMedGoogle Scholar
  26. 26.
    Wang P, Palese P, O’Neill RE (1997) The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza A virus nucleoprotein NP is a nonconventional nuclear localization signal. J Virol 71: 1850–1856PubMedGoogle Scholar
  27. 27.
    Cros JF, Garcia-Sastre A, Palese P (2005) An unconventional NLS is critical for the nuclear import of the influenza A virus nucleoprotein and ribonucleoprotein. Traffic 6: 205–213PubMedGoogle Scholar
  28. 28.
    Area E, Martin-Benito J, Gastaminza P, Torreira E, Valpuesta JM, Carrascosa JL, Ortin J (2004) 3D structure of the influenza virus polymerase complex: Localization of subunit domains. Proc Natl Acad Sci USA 101: 308–313PubMedGoogle Scholar
  29. 29.
    Jung TE, Brownlee GG (2006) A new promoter-binding site in the PB1 subunit of the influenza A virus polymerase. J Gen Virol 87: 679–688PubMedGoogle Scholar
  30. 30.
    Perez DR, Donis RO (2001) Functional analysis of PA binding by influenza A virus PB1: Effects on polymerase activity and viral infectivity. J Virol 75: 8127–8136PubMedGoogle Scholar
  31. 31.
    Poole E, Elton D, Medcalf L, Digard P (2004) Functional domains of the influenza A virus PB2 protein: Identification of NP-and PB1-binding sites. Virology 321: 120–133PubMedGoogle Scholar
  32. 32.
    Fechter P, Mingay L, Sharps J, Chambers A, Fodor E, Brownlee GG (2003) Two aromatic residues in the PB2 subunit of influenza A RNA polymerase are crucial for cap binding. J Biol Chem 278: 20381–20388PubMedGoogle Scholar
  33. 33.
    Krug RM, Bouloy M, Plotch SJ (1980) RNA primers and the role of host nuclear RNA polymerase II in influenza viral RNA transcription. Philos Trans R Soc Lond B Biol Sci 288: 359–370PubMedGoogle Scholar
  34. 34.
    Labadie K, Dos Santos Afonso E, Rameix-Welti MA, van der Werf S, Naffakh N (2007) Host-range determinants on the PB2 protein of influenza A viruses control the interaction between the viral polymerase and nucleoprotein in human cells. Virology 362: 271–282PubMedGoogle Scholar
  35. 35.
    Kawaguchi A, Naito T, Nagata K (2005) Involvement of influenza virus PA subunit in assembly of functional RNA polymerase complexes. J Virol 79: 732–744PubMedGoogle Scholar
  36. 36.
    Fodor E, Smith M (2004) The PA subunit is required for efficient nuclear accumulation of the PB1 subunit of the influenza A virus RNA polymerase complex. J Virol 78: 9144–9153PubMedGoogle Scholar
  37. 37.
    Li X, Palese P (1994) Characterization of the polyadenylation signal of influenza virus RNA. J Virol 68: 1245–1249PubMedGoogle Scholar
  38. 38.
    Luo GX, Luytjes W, Enami M, Palese P (1991) The polyadenylation signal of influenza virus RNA involves a stretch of uridines followed by the RNA duplex of the panhandle structure. J Virol 65: 2861–2867PubMedGoogle Scholar
  39. 39.
    Zheng H, Lee HA, Palese P, Garcia-Sastre A (1999) Influenza A virus RNA polymerase has the ability to stutter at the polyadenylation site of a viral RNA template during RNA replication. J Virol 73: 5240–5243PubMedGoogle Scholar
  40. 40.
    Ye Q, Krug RM, Tao YJ (2006) The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444: 1078–1082PubMedGoogle Scholar
  41. 41.
    Vreede FT, Brownlee GG (2007) Influenza virion-derived viral ribonucleoproteins synthesize both mRNA and cRNA in vitro. J Virol 81: 2196–2204PubMedGoogle Scholar
  42. 42.
    Baudin F, Petit I, Weissenhorn W, Ruigrok RW (2001) In vitro dissection of the membrane and RNP binding activities of influenza virus M1 protein. Virology 281: 102–108PubMedGoogle Scholar
  43. 43.
    Akarsu H, Burmeister WP, Petosa C, Petit I, Muller CW, Ruigrok RW, Baudin F (2003) Crystal structure of the M1 protein-binding domain of the influenza A virus nuclear export protein (NEP/NS2). EMBO J 22: 4646–4655PubMedGoogle Scholar
  44. 44.
    Gallagher PJ, Henneberry JM, Sambrook JF, Gething MJ (1992) Glycosylation requirements for intracellular transport and function of the hemagglutinin of influenza virus. J Virol 66: 7136–7145PubMedGoogle Scholar
  45. 45.
    Enami M, Sharma G, Benham C, Palese P (1991) An influenza virus containing nine different RNA segments. Virology 185: 291–298PubMedGoogle Scholar
  46. 46.
    Bancroft CT, Parslow TG (2002) Evidence for segment-nonspecific packaging of the influenza A virus genome. J Virol 76: 7133–7139PubMedGoogle Scholar
  47. 47.
    Watanabe T, Watanabe S, Noda T, Fujii Y, Kawaoka Y (2003) Exploitation of nucleic acid packaging signals to generate a novel influenza virus-based vector stably expressing two foreign genes. J Virol 77: 10575–10583PubMedGoogle Scholar
  48. 48.
    de Wit E, Spronken MI, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (2006) Evidence for specific packaging of the influenza A virus genome from conditionally defective virus particles lacking a polymerase gene. Vaccine 24: 6647–6650PubMedGoogle Scholar
  49. 49.
    Liang Y, Hong Y, Parslow TG (2005) cis-Acting packaging signals in the influenza virus PB1, PB2, and PA genomic RNA segments. J Virol 79: 10348–10355PubMedGoogle Scholar
  50. 50.
    Fujii K, Fujii Y, Noda T, Muramoto Y, Watanabe T, Takada A, Goto H, Horimoto T, Kawaoka Y (2005) Importance of both the coding and the segment-specific noncoding regions of the influenza A virus NS segment for its efficient incorporation into virions. J Virol 79: 3766–3774PubMedGoogle Scholar
  51. 51.
    Fujii Y, Goto H, Watanabe T, Yoshida T, Kawaoka Y (2003) Selective incorporation of influenza virus RNA segments into virions. Proc Natl Acad Sci USA 100: 2002–2007PubMedGoogle Scholar
  52. 52.
    Gog JR, Afonso ED, Dalton RM, Leclercq I, Tiley L, Elton D, von Kirchbach JC, Naffakh N, Escriou N, Digard P (2007) Codon conservation in the influenza A virus genome defines RNA packaging signals. Nucleic Acids Res 35:1897–1907PubMedGoogle Scholar
  53. 53.
    Schmitt AP, Lamb RA (2005) Influenza virus assembly and budding at the viral budozone. Adv Virus Res 64: 383–416PubMedGoogle Scholar
  54. 54.
    Chen BJ, Takeda M, Lamb RA (2005) Influenza virus hemagglutinin (H3 subtype) requires palmitoylation of its cytoplasmic tail for assembly: M1 proteins of two subtypes differ in their ability to support assembly. J Virol 79: 13673–13684PubMedGoogle Scholar
  55. 55.
    Zhang J, Pekosz A, Lamb RA (2000) Influenza virus assembly and lipid raft microdomains: A role for the cytoplasmic tails of the spike glycoproteins. J Virol 74: 4634–4644PubMedGoogle Scholar
  56. 56.
    Barman S, Adhikary L, Chakrabarti AK, Bernas C, Kawaoka Y, Nayak DP (2004) Role of transmembrane domain and cytoplasmic tail amino acid sequences of influenza A virus neuraminidase in raft association and virus budding. J Virol 78: 5258–5269PubMedGoogle Scholar
  57. 57.
    Carrasco M, Amorim MJ, Digard P (2004) Lipid raft-dependent targeting of the influenza A virus nucleoprotein to the apical plasma membrane. Traffic 5: 979–992PubMedGoogle Scholar
  58. 58.
    Bourmakina SV, Garcia-Sastre A (2003) Reverse genetics studies on the filamentous morphology of influenza A virus. J Gen Virol 84: 517–527PubMedGoogle Scholar
  59. 59.
    Elleman CJ, Barclay WS (2004) The M1 matrix protein controls the filamentous phenotype of influenza A virus. Virology 321: 144–153PubMedGoogle Scholar
  60. 60.
    Palese P, Tobita K, Ueda M, Compans RW (1974) Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology 61: 397–410PubMedGoogle Scholar
  61. 61.
    Mitnaul LJ, Matrosovich MN, Castrucci MR, Tuzikov AB, Bovin NV, Kobasa D, Kawaoka Y (2000) Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 74: 6015–6020PubMedGoogle Scholar
  62. 62.
    Colman PM (1994) Influenza virus neuraminidase: Structure, antibodies, and inhibitors. Protein Sci 3: 1687–1696PubMedGoogle Scholar
  63. 63.
    Fitch WM, Leiter JM, Li XQ, Palese P (1991) Positive Darwinian evolution in human influenza A viruses. Proc Natl Acad Sci USA 88: 4270–4274PubMedGoogle Scholar
  64. 64.
    Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, Fouchier RA (2004) Mapping the antigenic and genetic evolution of influenza virus. Science 305: 371–376PubMedGoogle Scholar
  65. 65.
    Bean WJ, Schell M, Katz J, Kawaoka Y, Naeve C, Gorman O, Webster RG (1992) Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 66: 1129–1138PubMedGoogle Scholar
  66. 66.
    Ferguson NM, Galvani AP, Bush RM (2003) Ecological and immunological determinants of influenza evolution. Nature 422: 428–433PubMedGoogle Scholar
  67. 67.
    Plotkin JB, Dushoff J, Levin SA (2002) Hemagglutinin sequence clusters and the antigenic evolution of influenza A virus. Proc Natl Acad Sci USA 99: 6263–6268PubMedGoogle Scholar
  68. 69.
    Horimoto T, Kawaoka Y (2005) Influenza: Lessons from past pandemics, warnings from current incidents. Nat Rev Microbiol 3: 591–600PubMedGoogle Scholar
  69. 70.
    Webster RG, Govorkova EA (2006) H5N1 influenza-Continuing evolution and spread. N Engl J Med 355: 2174–2177PubMedGoogle Scholar
  70. 71.
    Vines A, Wells K, Matrosovich M, Castrucci MR, Ito T, Kawaoka Y (1998) The role of influenza A virus hemagglutinin residues 226 and 228 in receptor specificity and host range restriction. J Virol 72: 7626–7631PubMedGoogle Scholar
  71. 72.
    Rogers GN, Paulson JC (1983) Receptor determinants of human and animal influenza virus isolates: Differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127: 361–373PubMedGoogle Scholar
  72. 73.
    Suzuki Y, Ito T, Suzuki T, Holland RE Jr, Chambers TM, Kiso M, Ishida H. Kawaoka Y (2000) Sialic acid species as a determinant of the host range of influenza A viruses. J Virol 74: 11825–11831PubMedGoogle Scholar
  73. 74.
    Rogers GN, Pritchett TJ, Lane JL, Paulson JC (1983) Differential sensitivity of human, avian, and equine influenza A viruses to a glycoprotein inhibitor of infection: Selection of receptor specific variants. Virology 131: 394–408PubMedGoogle Scholar
  74. 75.
    Rogers GN, D’Souza BL (1989) Receptor binding properties of human and animal H1 influenza virus isolates. Virology 173: 317–322PubMedGoogle Scholar
  75. 76.
    Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006) Infection of human airway epithelium by human and avian strains of influenza A virus. J Virol 80: 8060–8068PubMedGoogle Scholar
  76. 77.
    Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci USA 101: 4620–4624PubMedGoogle Scholar
  77. 78.
    Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Avian flu: Influenza virus receptors in the human airway. Nature 440: 435–436PubMedGoogle Scholar
  78. 79.
    Ibricevic A, Pekosz A, Walter MJ, Newby C, Battaile JT, Brown EG, Holtzman MJ, Brody SL (2006) Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells. J Virol 80: 7469–7480PubMedGoogle Scholar
  79. 80.
    van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T (2006) H5N1 virus attachment to lower respiratory tract. Science 312: 399PubMedGoogle Scholar
  80. 81.
    de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau NV, Khanh TH, Dong VC et al (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 12: 1203–1207PubMedGoogle Scholar
  81. 82.
    Kandun IN, Wibisono H, Sedyaningsih ER, Yusharmen, Hadisoedarsuno W, Purba W, Santoso H, Septiawati C, Tresnaningsih E, Heriyanto B et al (2006) Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med 355: 2186–2194PubMedGoogle Scholar
  82. 83.
    Oner AF, Bay A, Arslan S, Akdeniz H, Sahin HA, Cesur Y, Epcacan S, Yilmaz N, Deger I, Kizilyildiz B et al (2006) Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 355: 2179–2185PubMedGoogle Scholar
  83. 84.
    Butt KM, Smith GJ, Chen H, Zhang LJ, Leung YH, Xu KM, Lim W, Webster RG, Yuen KY, Peiris JS, Guan Y (2005) Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J Clin Microbiol 43: 5760–5767PubMedGoogle Scholar
  84. 85.
    Koopmans M, Wilbrink B, Conyn M, Natrop G, van der Nat H, Vennema H, Meijer A, van Steenbergen J, Fouchier R, Osterhaus A, Bosman A (2004) Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 363: 587–593PubMedGoogle Scholar
  85. 86.
    Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, Munster V, Kuiken T, Rimmelzwaan GF, Schutten M, Van Doornum GJ et al (2004) Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci USA 101: 1356–1361PubMedGoogle Scholar
  86. 87.
    Uiprasertkul M, Puthavathana P, Sangsiriwut K, Pooruk P, Srisook K, Peiris M, Nicholls JM, Chokephaibulkit K, Vanprapar N, Auewarakul P (2005) Influenza A H5N1 replication sites in humans. Emerg Infect Dis 11: 1036–1041PubMedGoogle Scholar
  87. 88.
    Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006) Infection of human airway epithelium by human and avian strains of influenza A virus. J Virol 80: 8060–8068PubMedGoogle Scholar
  88. 89.
    Nicholls JM, Chan MC, Chan WY, Wong HK, Cheung CY, Kwong DL, Wong MP, Chui WH, Poon LL, Tsao SW et al (2007) Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat Med 13: 147–149PubMedGoogle Scholar
  89. 90.
    Yamada S, Suzuki Y, Suzuki T, Le MQ, Nidom CA, Sakai-Tagawa Y, Muramoto Y, Ito M, Kiso M, Horimoto T et al (2006) Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444: 378–382PubMedGoogle Scholar
  90. 91.
    Gambaryan AS, Tuzikov AB, Bovin NV, Yamnikova SS, Lvov DK, Webster RG, Matrosovich MN (2003) Differences between influenza virus receptors on target cells of duck and chicken and receptor specificity of the 1997 H5N1 chicken and human influenza viruses from Hong Kong. Avian Dis 47: 1154–1160PubMedGoogle Scholar
  91. 92.
    Wan H, Perez DR (2006) Quail carry sialic acid receptors compatible with binding of avian and human influenza viruses. Virology. 346: 278–286PubMedGoogle Scholar
  92. 93.
    Shu LL, Lin YP, Wright SM, Shortridge KF, Webster RG (1994) Evidence for interspecies transmission and reassortment of influenza A viruses in pigs in southern China. Virology 202: 825–833PubMedGoogle Scholar
  93. 94.
    Castrucci MR, Donatelli I, Sidoli L, Barigazzi G, Kawaoka Y, Webster RG (1993) Genetic reassortment between avian and human influenza A viruses in Italian pigs. Virology 193: 503–506PubMedGoogle Scholar
  94. 95.
    Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP (2005) Does this patient have influenza? JAMA 293: 987–997PubMedGoogle Scholar
  95. 96.
    Bhat N, Wright JG, Broder KR, Murray EL, Greenberg ME, Glover MJ, Likos AM, Posey DL, Klimov A, Lindstrom SE et al (2005) Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med 353: 2559–2567PubMedGoogle Scholar
  96. 97.
    Nolte KB, Alakija P, Oty G, Shaw MW, Subbarao K, Guarner J, Shieh WJ, Dawson JE, Morken T, Cox NJ, Zaki SR (2000) Influenza A virus infection complicated by fatal myocarditis. Am J Forensic Med Pathol 21: 375–379PubMedGoogle Scholar
  97. 98.
    Davis MM, Taubert K, Benin AL, Brown DW, Mensah GA, Baddour LM, Dunbar S, Krumholz HM, American Heart Association, American College of Cardiology et al (2006) Influenza vaccination as secondary prevention for cardiovascular disease: A science advisory from the American Heart Association/ American College of Cardiology. J Am Coll Cardiol 48: 1498–1502Google Scholar
  98. 99.
    Jaimovich DG, Kumar A, Shabino CL, Formoli R (1992) Influenza B virus infection associated with non-bacterial septic shock-like illness. J Infect 25: 311–315PubMedGoogle Scholar
  99. 100.
    Guarner J, Paddock CD, Shieh WJ, Packard MM, Patel M, Montague JL, Uyeki TM, Bhat N, Balish A, Lindstrom S et al (2006) Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 2003-2004 season. Clin Infect Dis 43: 132–140PubMedGoogle Scholar
  100. 101.
    Chan PK (2002) Outbreak of avian influenza A (H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 34: S58–64Google Scholar
  101. 102.
    Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH et al (2005) Avian influenza A (H5N1) infection in humans. N Engl J Med 353: 1374–1385PubMedGoogle Scholar
  102. 103.
    Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, Lochindarat S, Srisan P, Suwan P, Osotthanakorn Y et al (2005) Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 11: 201–209PubMedGoogle Scholar
  103. 104.
    Ng WF, To KF, Lam WW, Ng TK, Lee KC (2006) The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1-A review. Hum Pathol 37: 381–390PubMedGoogle Scholar
  104. 105.
    To KF, Chan PK, Chan KF, Lee WK, Lam WY, Wong KF, Tang NL, Tsang DN, Sung RY, Buckley TA et al (2001) Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 63: 242–246PubMedGoogle Scholar
  105. 106.
    Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS (2005) Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6: 135PubMedGoogle Scholar
  106. 107.
    Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, Chignard M, Si-Tahar M (2006) Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2: e53Google Scholar
  107. 108.
    Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293: 1840–1842PubMedGoogle Scholar
  108. 109.
    Salomon R, Franks J, Govorkova EA, Ilyushina NA, Yen HL, Hulse-Post DJ, Humberd J, Trichet M, Rehg JE, Webby RJ et al (2006) The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04. J Exp Med 203: 689–697PubMedGoogle Scholar
  109. 110.
    Maines TR, Lu XH, Erb SM, Edwards L, Guarner J, Greer PW, Nguyen DC, Szretter KJ, Chen LM, Thawatsupha P et al (2005) Avian influenza (H5N1) viruses isolated from humans in Asia in 2004 exhibit increased virulence in mammals. J Virol 79: 11788–11800PubMedGoogle Scholar
  110. 111.
    Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P (2005) Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog 1: e4Google Scholar
  111. 112.
    Zamarin D, Ortigoza MB, Palese P (2006) Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 80: 7976–7983PubMedGoogle Scholar
  112. 113.
    Garcia-Sastre A, Biron CA (2006) Type 1 interferons and the virus-host relationship: A lesson in detente. Science 312: 879–882PubMedGoogle Scholar
  113. 114.
    Li Z, Jiang Y, Jiao P, Wang A, Zhao F, Tian G, Wang X, Yu K, Bu Z, Chen H (2006) The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J Virol 80: 11115–11123PubMedGoogle Scholar
  114. 115.
    Obenauer JC, Denson J, Mehta PK, Su X, Mukatira S, Finkelstein DB, Xu X, Wang J, Ma J, Fan Y et al (2006) Large-scale sequence analysis of avian influenza isolates. Science 311: 1576–1580PubMedGoogle Scholar
  115. 116.
    Li S, Schulman J, Itamura S, Palese P (1993) Glycosylation of neuraminidase determines the neurovirulence of influenza A/WSN/33 virus. J Virol 67: 6667–6673PubMedGoogle Scholar
  116. 117.
    Lofgren E, Fefferman N, Naumov YN, Gorski J, Naumova EN (2007) Influenza seasonality: Underlying causes and modeling theories. J Virol 81: 5429–5436PubMedGoogle Scholar
  117. 118.
    Stone L, Olinky R, Huppert A (2007) Seasonal dynamics of recurrent epidemics. Nature 446: 533–536PubMedGoogle Scholar
  118. 119.
    Tellier R (2006) Review of aerosol transmission of influenza A virus. Emerg Infect Dis 12: 1657–1662PubMedGoogle Scholar
  119. 120.
    Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M (2007) Transmission of influenza A in human beings. Lancet Infect Dis 7: 257–265PubMedGoogle Scholar
  120. 121.
    Lowen AC, Mubareka S, Tumpey TM, Garcia-Sastre A, Palese P (2006) The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci USA 103: 9988–9992PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Samira Mubareka
    • 1
  • Peter Palese
    • 1
  1. 1.Department of MicrobiologyMount Sinai School of MedicineNew YorkUSA

Personalised recommendations