Emergence of Influenza Viruses and Crossing the Species Barrier

Zeynep A. Koçer; Jeremy C. Jones; Robert G. Webster

doi:10.1128/microbiolspec.OH-0010-2012

Chapter 8 : Emergence of Influenza Viruses and Crossing the Species Barrier

Authors: Zeynep A. Koçer¹, Jeremy C. Jones², Robert G. Webster³

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Affiliations: 1: Department of Infectious Diseases, Division of Virology, St. Jude Children’s Research Hospital, Memphis, TN 38105; 2: Department of Infectious Diseases, Division of Virology, St. Jude Children’s Research Hospital, Memphis, TN 38105; 3: Department of Infectious Diseases, Division of Virology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Content Type: Monograph

Publication Year: 2014

Category: General Interest; Environmental Microbiology

Book DOI: 10.1128/9781555818432

Chapter DOI: 10.1128/microbiolspec.OH-0010-2012

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Abstract:

Influenza is a respiratory disease affecting humans, a limited number of other mammals, and birds. Of the three genera of orthomyxoviruses affecting humans, influenza viruses B and C established permanent lineages in ancient times, whereas influenza A viruses continue to emerge from zoonotic reservoirs and cause annual epidemics and, at irregular intervals, pandemics. Aquatic birds of the world are natural reservoirs for 16 of the 17 known influenza subtypes, and 1 subtype has been characterized from bats. Only three hemagglutinin subtypes (H1, H2, and H3) have caused pandemics in humans; the H1 and H3 subtypes are currently circulating in swine; and the H3 subtype is currently the only remaining epidemic subtype in horses and appears to be establishing a permanent lineage in dogs. All 16 subtypes of influenza viruses in the aquatic bird reservoir occur as low-pathogenicity strains that replicate predominantly in the intestinal tract and cause limited symptoms of overt disease. Subtypes H5 and H7 have the unique ability to evolve into highly pathogenic strains that are lethal in gallinaceous poultry and have the propensity for transitory interspecies transmission to mammals.

Citation: Koçer Z, Jones J, Webster R. 2014. Emergence of Influenza Viruses and Crossing the Species Barrier, p 115-135. In Atlas R, Maloy S (ed), One Health. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.OH-0010-2012

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Emergence of Influenza Viruses and Crossing the Species Barrier

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Figure 1

Influenza A virus structure and molecular determinants conferring pathogenesis and host range. Influenza A is an enveloped, negative-sense RNA virus with an eight-segment genome. The virion is studded with surface glycoproteins HA and NA and the M2 ion channel. Pathogenesis and transmission are mediated by multiple genes. Predominant molecular characteristics conferring these traits are diagrammed on each gene product above and as follows. HA: Sialic acid binding restrictions are partially mediated by residues 226 and 228 at the receptor binding site. The presence or absence of a multibasic cleavage site influences the cleavability of the virus by a broader range of enzymes, which leads to high pathogenicity of the virus in host species by causing a systemic infection ( 13 ). NA: Sialidase activity is specific to the binding restrictions of the HA protein and cleaves sialic acid residues, permitting release ( 14 ); deletions in the stalk region may confer adaptation to domestic poultry ( 13 ). PB2: Positions 627 ( 76 ) and 701 ( 22 ) are associated with enhanced replication in mammals. The immunomodulatory potential of changes or expression of the following proteins may contribute to early and productive replication in a new host. NS1: Position F92E/D confers cytokine resistance in mammalian hosts ( 77 ). PB1-F2: Position N66S is associated with increased virulence and cytokine dysregulation in mice ( 78 ). PA-X: Expression of this protein may lessen immunopathology during viral infection ( 3 ). doi:10.1128/microbiolspec.OH-0010-2012.f1

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Figure 1

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Figure 2

Transmission and host range of influenza A viruses. Wild aquatic birds, and possibly bats, serve as the reservoir for influenza A viruses. Well-established transmission events from the reservoir to other host species are represented by solid lines with directionality indicated by arrowheads. Less frequent transmission or events for which data are anecdotal are represented by dotted lines. *bats. Molecular characterization only. doi:10.1128/microbiolspec.OH-0010-2012.f2

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Figure 2

References

/content/book/10.1128/9781555818432.chap8

1. Strauss JH,, Strauss EG . 2002. Viruses and Human Disease, p 147– 156. Academic Press, San Diego, CA.

2. Chen W,, Calvo PA,, Malide D,, Gibbs J,, Schubert U,, Bacik I,, Basta S,, O’Neill R,, Schickli J,, Palese P,, Henklein P,, Bennink JR,, Yewdell JW . 2001. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7 : 1306– 1312. [PubMed] [CrossRef]

3. Jagger BW,, Wise HM,, Kash JC,, Walters KA,, Wills NM,, Xiao YL,, Dunfee RL,, Schwartzman LM,, Ozinsky A,, Bell GL,, Dalton RM,, Lo A,, Efstathiou S,, Atkins JF,, Firth AE,, Taubenberger JK,, Digard P . 2012. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337 : 199– 204. [PubMed] [CrossRef]

4. Steinhauer DA,, Skehel JJ . 2002. Genetics of influenza viruses. Annu Rev Genet 36 : 305– 332. [PubMed] [CrossRef]

5. Webster RG,, Bean WJ,, Gorman OT,, Chambers TM,, Kawaoka Y . 1992. Evolution and ecology of influenza A viruses. Microbiol Rev 56 : 152– 179.

6. Smith FL,, Palese P, . 1989. Variation in influenza virus genes: epidemiological, pathogenic, and evolutionary consequences, p 319– 359. In Krug RM (ed), The Influenza Viruses. Plenum, New York, NY.

7. Olsen B,, Munster VJ,, Wallensten A,, Waldenström J,, Osterhaus AD,, Fouchier RA . 2006. Global patterns of influenza A virus in wild birds. Science 312 : 384– 388. [PubMed] [CrossRef]

8. Tong S,, Li Y,, Rivailler P,, Conrardy C,, Castillo DA,, Chen LM,, Recuenco S,, Ellison JA,, Davis CT,, York IA,, Turmelle AS,, Moran D,, Rogers S,, Shi M,, Tao Y,, Weil MR,, Tang K,, Rowe LA,, Sammons S,, Xu X,, Frace M,, Lindblade KA,, Cox NJ,, Anderson LJ,, Rupprecht CE,, Donis RO . 2012. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci USA 109 : 4269– 4274. [PubMed] [CrossRef]

9. Krauss S,, Obert CA,, Franks J,, Walker D,, Jones K,, Seiler P,, Niles L,, Pryor SP,, Obenauer JC,, Naeve CW,, Widjaja L,, Webby RJ,, Webster RG . 2007. Influenza in migratory birds and evidence of limited intercontinental virus exchange. PLoS Pathog 3 : e167. [PubMed] [CrossRef]

10. Fuller TL,, Saatchi SS,, Curd EE,, Toffelmier E,, Thomassen HA,, Buermann W,, DeSante DF,, Nott MP,, Saracco JF,, Ralph C,, Alexander JD,, Pollinger JP,, Smith TB . 2010. Mapping the risk of avian influenza in wild birds in the US. BMC Infect Dis 10 : 187. [PubMed] [CrossRef]

11. Nestorowicz A,, Kawaoka Y,, Bean WJ,, Webster RG . 1987. Molecular analysis of the hemagglutinin genes of Australian H7N7 influenza viruses: role of passerine birds in maintenance or transmission? Virology 160 : 411– 418. [PubMed]

12. Pereda AJ,, Uhart M,, Perez AA,, Zaccagnini ME,, La Sala L,, Decarre J,, Goijman A,, Solari L,, Suarez R,, Craig MI,, Vagnozzi A,, Rimondi A,, König G,, Terrera MV,, Kaloghlian A,, Song H,, Sorrell EM,, Perez DR . 2008. Avian influenza virus isolated in wild waterfowl in Argentina: evidence of a potentially unique phylogenetic lineage in South America. Virology 378 : 363– 370. [PubMed] [CrossRef]

13. Neumann G,, Kawaoka Y . 2006. Host range restriction and pathogenicity in the context of influenza pandemic. Emerg Infect Dis 12 : 881– 886. [PubMed]

14. Kuiken T,, Holmes EC,, McCauley J,, Rimmelzwaan GF,, Williams CS,, Grenfell BT . 2006. Host species barriers to influenza virus infections. Science 312 : 394– 397. [PubMed] [CrossRef]

15. Scull MA,, Gillim-Ross L,, Santos C,, Roberts KL,, Bordonali E,, Subbarao K,, Barclay WS,, Pickles RJ . 2009. Avian influenza virus glycoproteins restrict virus replication and spread through human airway epithelium at temperatures of the proximal airways. PLoS Pathog 5 : e1000424. [PubMed] [CrossRef]

16. Ito T,, Kawaoka Y . 2000. Host-range barrier of influenza A viruses. Vet Microbiol 74 : 71– 75.

17. Fukuyama S,, Kawaoka Y . 2011. The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol 23 : 481– 486. [PubMed]

18. Baigent SJ,, McCauley JW . 2003. Influenza type A in humans, mammals and birds: determinants of virus virulence, host-range and interspecies transmission. Bioessays 25 : 657– 671. [PubMed] [CrossRef]

19. Alexander DJ . 2000. A review of avian influenza in different bird species. Vet Microbiol 74 : 3– 13. [PubMed]

20. Suarez DL,, Senne DA,, Banks J,, Brown IH,, Essen SC,, Lee CW,, Manvell RJ,, Mathieu-Benson C,, Moreno V,, Pedersen JC,, Panigrahy B,, Rojas H,, Spackman E,, Alexander DJ . 2004. Recombination resulting in virulence shift in avian influenza outbreak, Chile. Emerg Infect Dis 10 : 693– 699. [PubMed] [CrossRef]

21. Pasick J,, Handel K,, Robinson J,, Copps J,, Ridd D,, Hills K,, Kehler H,, Cottam-Birt C,, Neufeld J,, Berhane Y,, Czub S . 2005. Intersegmental recombination between the haemagglutinin and matrix genes was responsible for the emergence of a highly pathogenic H7N3 avian influenza virus in British Columbia. J Gen Virol 86 : 727– 731. [PubMed] [CrossRef]

22. Li Z,, Chen H,, Jiao P,, Deng G,, Tian G,, Li Y,, Hoffmann E,, Webster RG,, Matsuoka Y,, Yu K . 2005. Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 79 : 12058– 12064. [PubMed] [CrossRef]

23. Spickler AR,, Trampel DW,, Roth JA . 2008. The onset of virus shedding and clinical signs in chickens infected with high-pathogenicity and low-pathogenicity avian influenza viruses. Avian Pathol 37 : 555– 577. [PubMed] [CrossRef]

24. Food and Agriculture Organization of the United Nations (FAO) . 2012. Understanding avian influenza. Agriculture Department, Animal Production and Health Division, FAO, Rome, Italy. http://www.fao.org/avianflu/documents/key_ai/key_book_preface.htm (last accessed July 23, 2012).

25. Kuntz-Simon G,, Madec F . 2009. Genetic and antigenic evolution of swine influenza viruses in Europe and evaluation of their zoonotic potential. Zoonoses Public Health 56 : 310– 325. [PubMed] [CrossRef]

26. Olsen CW . 2002. The emergence of novel swine influenza viruses in North America. Virus Res 85 : 199– 210. [PubMed]

27. Ma W,, Lager KM,, Vincent AL,, Janke BH,, Gramer MR,, Richt JA . 2009. The role of swine in the generation of novel influenza viruses. Zoonoses Public Health 56 : 326– 337. [PubMed] [CrossRef]

28. Myers KP,, Olsen CW,, Gray GC . 2007. Cases of swine influenza in humans: a review of the literature. Clin Infect Dis 44 : 1084– 1088. [PubMed] [CrossRef]

29. Christman MC,, Kedwaii A,, Xu J,, Donis RO,, Lu G . 2011. Pandemic (H1N1) 2009 virus revisited: an evolutionary retrospective. Infect Genet Evol 11 : 803– 811. [PubMed] [CrossRef]

30. Taubenberger JK,, Reid AH,, Janczewski TA,, Fanning TG . 2001. Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus. Philos Trans R Soc Lond B Biol Sci 356 : 1829– 1839. [PubMed] [CrossRef]

31. Yoon KJ,, Schwartz K,, Sun D,, Zhang J,, Hildebrandt H . 2012. Naturally occurring Influenza A virus subtype H1N2 infection in a Midwest United States mink ( Mustela vison) ranch. J Vet Diagn Invest 24 : 388– 391. [PubMed] [CrossRef]

32. Komadina N,, Roque V,, Thawatsupha P,, Rimando-Magalong J,, Waicharoen S,, Bomasang E,, Sawanpanyalert P,, Rivera M,, Iannello P,, Hurt AC,, Barr IG . 2007. Genetic analysis of two influenza A (H1) swine viruses isolated from humans in Thailand and the Philippines. Virus Genes 35 : 161– 165. [PubMed] [CrossRef]

33. Suarez DL,, Woolcock PR,, Bermudez AJ,, Senne DA . 2002. Isolation from turkey breeder hens of a reassortant H1N2 influenza virus with swine, human, and avian lineage genes. Avian Dis 46 : 111– 121. [PubMed]

34. Ma W,, Vincent AL,, Gramer MR,, Brockwell CB,, Lager KM,, Janke BH,, Gauger PC,, Patnayak DP,, Webby RJ,, Richt JA . 2007. Identification of H2N3 influenza A viruses from swine in the United States. Proc Natl Acad Sci USA 104 : 20949– 20954. [PubMed] [CrossRef]

35. Cullinane A,, Elton D,, Mumford J . 2010. Equine influenza—surveillance and control. Influenza Other Respi Viruses 4 : 339– 344. [PubMed] [CrossRef]

36. Elton D,, Bryant N . 2011. Facing the threat of equine influenza. Equine Vet J 43 : 250– 258. [PubMed] [CrossRef]

37. Daly JM,, MacRae S,, Newton JR,, Wattrang E,, Elton DM . 2011. Equine influenza: a review of an unpredictable virus. Vet J 189 : 7– 14. [PubMed] [CrossRef]

38. Sovinova O,, Tumova B,, Pouska F,, Nemec J . 1958. Isolation of a virus causing respiratory disease in horses. Acta Virol 2 : 52– 61. [PubMed]

39. Webster RG . 1993. Are equine 1 influenza viruses still present in horses? Equine Vet J 25 : 537– 538. [PubMed]

40. Guo Y,, Wang M,, Kawaoka Y,, Gorman O,, Ito T,, Saito T,, Webster RG . 1992. Characterization of a new avian-like influenza A virus from horses in China. Virology 188 : 245– 255. [PubMed]

41. Kasel JA,, Couch RB . 1969. Experimental infection in man and horses with influenza A viruses. Bull W H O 41 : 447– 452. [PubMed]

42. Hinshaw VS,, Bean WJ,, Webster RG,, Rehg JE,, Fiorelli P,, Early G,, Geraci JR,, St Aubin DJ . 1984. Are seals frequently infected with avian influenza viruses? J Virol 51 : 863– 865. [PubMed]

43. Callan RJ,, Early G,, Kida H,, Hinshaw VS . 1995. The appearance of H3 influenza viruses in seals. J Gen Virol 76( Pt 1) : 199– 203. [PubMed]

44. Blanc A,, Ruchansky D,, Clara M,, Achaval F,, Le Bas A,, Arbiza J . 2009. Serologic evidence of influenza A and B viruses in South American fur seals ( Arctocephalus australis). J Wildl Dis 45 : 519– 521. [PubMed] [CrossRef]

45. Nielsen O,, Clavijo A,, Boughen JA . 2001. Serologic evidence of influenza A infection in marine mammals of Arctic Canada. J Wildl Dis 37 : 820– 825. [PubMed] [CrossRef]

46. Hinshaw VS,, Bean WJ,, Geraci J,, Fiorelli P,, Early G,, Webster RG . 1986. Characterization of two influenza A viruses from a pilot whale. J Virol 58 : 655– 656. [PubMed]

47. Lvov DK,, Zdanov VM,, Sazonov AA,, Braude NA,, Vladimirtceva EA,, Agafonova LV,, Skljanskaja EI,, Kaverin NV,, Reznik VI,, Pysina TV,, Oserovic AM,, Berzin AA,, Mjasnikova IA,, Podcernjaeva RY,, Klimenko SM,, Andrejev VP,, Yakhno MA . 1978. Comparison of influenza viruses isolated from man and from whales. Bull W H O 56 : 923– 930. [PubMed]

48. Anthony SJ,, St Leger JA,, Pugliares K,, Ip HS,, Chan JM,, Carpenter ZW,, Navarrete-Macias I,, Sanchez-Leon M,, Saliki JT,, Pedersen J,, Karesh W,, Daszak P,, Rabadan R,, Rowles T,, Lipkin WI . 2012. Emergence of fatal avian influenza in New England harbor seals. MBio 3 : e00166-12. [PubMed] [CrossRef]

49. Gagnon CA,, Spearman G,, Hamel A,, Godson DL,, Fortin A,, Fontaine G,, Tremblay D . 2009. Characterization of a Canadian mink H3N2 influenza A virus isolate genetically related to triple reassortant swine influenza virus. J Clin Microbiol 47 : 796– 799. [PubMed] [CrossRef]

50. Harder TC,, Vahlenkamp TW . 2010. Influenza virus infections in dogs and cats. Vet Immunol Immunopathol 134 : 54– 60. [PubMed] [CrossRef]

51. Clark NM,, Lynch JP III . 2011. Influenza: epidemiology, clinical features, therapy, and prevention. Semin Respir Crit Care Med 32 : 373– 392. [PubMed] [CrossRef]

52. Peiris JS,, Cheung CY,, Leung CY,, Nicholls JM . 2009. Innate immune responses to influenza A H5N1: friend or foe? Trends Immunol 30 : 574– 584. [PubMed] [CrossRef]

53. Nicholson KG,, Wood JM,, Zambon M . 2003. Influenza. Lancet 362 : 1733– 1745. [PubMed] [CrossRef]

54. Shanks GD,, Brundage JF . 2012. Pathogenic responses among young adults during the 1918 influenza pandemic. Emerg Infect Dis 18 : 201– 207. [PubMed] [CrossRef]

55. Reid AH,, Fanning TG,, Hultin JV,, Taubenberger JK . 1999. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci USA 96 : 1651– 1656. [PubMed]

56. Taubenberger JK,, Hultin JV,, Morens DM . 2007. Discovery and characterization of the 1918 pandemic influenza virus in historical context. Antivir Ther 12( 4 Pt B) : 581– 591. [PubMed]

57. Horimoto T,, Kawaoka Y . 2005. Influenza: lessons from past pandemics, warnings from current incidents. Nat Rev Microbiol 3 : 591– 600. [PubMed] [CrossRef]

58. Pada S,, Tambyah PA . 2011. Overview/reflections on the 2009 H1N1 pandemic. Microbes Infect 13 : 470– 478. [PubMed] [CrossRef]

59. Capua I,, Alexander DJ . 2007. Animal and human health implications of avian influenza infections. Biosci Rep 27 : 359– 372. [PubMed] [CrossRef]

60. de Jong JC,, Claas EC,, Osterhaus AD,, Webster RG,, Lim WL . 1997. A pandemic warning? Nature 389 : 554. [PubMed] [CrossRef]

61. Kung NY,, Morris RS,, Perkins NR,, Sims LD,, Ellis TM,, Bissett L,, Chow M,, Shortridge KF,, Guan Y,, Peiris MJ . 2007. Risk for infection with highly pathogenic influenza A virus (H5N1) in chickens, Hong Kong, 2002. Emerg Infect Dis 13 : 412– 418. [PubMed] [CrossRef]

62. Chen H,, Deng G,, Li Z,, Tian G,, Li Y,, Jiao P,, Zhang L,, Liu Z,, Webster RG,, Yu K . 2004. The evolution of H5N1 influenza viruses in ducks in southern China. Proc Natl Acad Sci USA 101 : 10452– 10457. [PubMed] [CrossRef]

63. Imai M,, Watanabe T,, Hatta M,, Das SC,, Ozawa M,, Shinya K,, Zhong G,, Hanson A,, Katsura H,, Watanabe S,, Li C,, Kawakami E,, Yamada S,, Kiso M,, Suzuki Y,, Maher EA,, Neumann G,, Kawaoka Y . 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486 : 420– 428. [PubMed] [CrossRef]

64. Herfst S,, Schrauwen EJ,, Linster M,, Chutinimitkul S,, de Wit E,, Munster VJ,, Sorrell EM,, Bestebroer TM,, Burke DF,, Smith DJ,, Rimmelzwaan GF,, Osterhaus AD,, Fouchier RA . 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336 : 1534– 1541. [PubMed] [CrossRef]

65. Ellebedy AH,, Webby RJ . 2009. Influenza vaccines. Vaccine 27( Suppl 4) : D65– D68. [PubMed] [CrossRef]

66. Schultz-Cherry S,, Jones JC . 2010. Influenza vaccines: the good, the bad, and the eggs. Adv Virus Res 77 : 63– 84. [PubMed] [CrossRef]

67. Szucs TD . 1999. Influenza. The role of burden-of-illness research. Pharmacoeconomics 16( Suppl 1) : 27– 32. [PubMed]

68. Kapczynski DR,, Swayne DE . 2009. Influenza vaccines for avian species. Curr Top Microbiol Immunol 333 : 133– 152. [PubMed] [CrossRef]

69. Vincent AL,, Ma W,, Lager KM,, Janke BH,, Richt JA . 2008. Swine influenza viruses: a North American perspective. Adv Virus Res 72 : 127– 154. [PubMed] [CrossRef]

70. US Department of Agriculture Animal and Plant Health Inspection Service (APHIS) . APHIS issues conditional license for canine influenza virus vaccine. June 23, 2009. APHIS, Washington, DC. http://www.aphis.usda.gov/newsroom/content/2009/06/caninevacc.shtml (last accessed July 31, 2012).

71. Saladino R,, Barontini M,, Crucianelli M,, Nencioni L,, Sgarbanti R,, Palamara AT . 2010. Current advances in anti-influenza therapy. Curr Med Chem 17 : 2101– 2140. [PubMed]

72. World Health Organization (WHO) . 2005. Use of antiviral drugs in poultry, a threat to their effectiveness for the treatment of human avian influenza. November 11, 2005. WHO, Geneva, Switzerland. http://www.who.int/foodsafety/micro/avian_antiviral/en/ (last accessed July 31, 2012).

73. Das K . 2012. Antivirals targeting influenza A virus. J Med Chem 55 : 6263– 6277. [PubMed] [CrossRef]

74. Dowdle WR . 2006. Influenza pandemic periodicity, virus recycling, and the art of risk assessment. Emerg Infect Dis 12 : 34– 39. [PubMed] [CrossRef]

75. Centers for Disease Control and Prevention (CDC) . 2012. Influenza Risk Assessment Tool (IRAT). June 21, 2012. CDC, Atlanta, GA. http://www.cdc.gov/flu/pandemic-resources/tools/risk-assessment.htm (last accessed July 25, 2012).

76. Shinya K,, Hamm S,, Hatta M,, Ito H,, Ito T,, Kawaoka Y . 2004. PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology 320 : 258– 266. [PubMed] [CrossRef]

77. Seo SH,, Hoffmann E,, Webster RG . 2002. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat Med 8 : 950– 954. [PubMed] [CrossRef]

78. Conenello GM,, Zamarin D,, Perrone LA,, Tumpey T,, Palese P . 2007. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog 3 : 1414– 1421. [PubMed] [CrossRef]