New threats from H7N9 influenza virus: Spread and evolution of high- and lowpathogenicity variants with high genomic diversity in wave five

Journal of Virology

Volumn 92, Issue 11, 2018, Pages

  Quan, Chuansong ^a,b   Shi, Weifeng ^c   Yang, Yang ^d   Yang, Yongchun ^e   Liu, Xiaoqing ^f   Xu, Wen ^g   Li, Hong ^g   Li, Juan ^c   Wang, Qianli ^h   Tong, Zhou ^b   Wong, Gary ^b,d   Zhang, Cheng ^b   Ma, Sufang ^b   Ma, Zhenghai ⁱ   Fu, Guanghua ^j   Zhang, Zewu ^k   Huang, Yu ^j   Song, Houhui ^e   Yang, Liuqing ^d   Liu, William J ^a   Liu, Yingxia ^d   Liu, Wenjun ^b   Gao, George F ^a,b,d   Bi, Yuhai ^b,d   more..

^a CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION   (China)

^b INSTITUTE OF MICROBIOLOGY   (China)

^c SHANDONG PROVINCIAL HOSPITAL AFFILIATED TO SHANDONG FIRST MEDICAL UNIVERSITY   (China)

^d SHENZHEN THIRD PEOPLE S HOSPITAL   (China)

^e ZHEJIANG A F UNIVERSITY   (China)

^f Jiangxi Province Center for Disease Control and Prevention   (China)

^g YUNNAN PROVINCIAL CENTER FOR DISEASE CONTROL AND PREVENTION   (China)

^h FUDAN UNIVERSITY   (China)

ⁱ XINJIANG UNIVERSITY   (China)

^j INSTITUTE OF PLANT PROTECTION   (China)

^k Dongguan Municipal Center for Disease Control and Prevention   (China)

more..

Author keywords

Avian influenza virus; Dynamic reassortment; Evolution; Genetic diversity; H7N9; HPAIV; Origin; Wave five

Indexed keywords

ALANINE; AMINO ACID DERIVATIVE; ARGININE; GLUTAMIC ACID; LYSINE; LYSYLARGINYLTHREONYLALANINE; LYSYLARGINYLTHREONYLALANYLARGININE; LYSYLARGINYLTHREONYLALANYLGLYCINE; PROLYLLYSYLARGINYLLYSYLARGINYLALANYLALANYLARGININE; PROLYLLYSYLARGINYLLYSYLARGINYLALANYLALANYLGLYCINE; PROLYLLYSYLARGINYLLYSYLARGINYLTHREONYLALANYLARGININE; PROLYLLYSYLARGINYLLYSYLARGINYLTHREONYLALANYLGLYCINE; PROLYLLYSYLGLYCYLLYSYLARGINYLISOLEUCYLALANYLARGININE; PROLYLLYSYLGLYCYLLYSYLARGINYLISOLEUCYLALANYLGLYCINE; SIALIDASE INHIBITOR; UNCLASSIFIED DRUG; VALINE; INFLUENZA VIRUS HEMAGGLUTININ; SIALIDASE;

ANTIVIRAL RESISTANCE; ARTICLE; AVIAN INFLUENZA; CHINA; CONTROLLED STUDY; GENE INSERTION; GENETIC ANALYSIS; GENETIC REASSORTMENT; GENETIC VARIABILITY; GENOTYPE; GEOGRAPHIC DISTRIBUTION; HUMAN; INFLUENZA A VIRUS (H7N9); INFLUENZA A VIRUS (H9N2); LIFE THREAT; MOLECULAR DYNAMICS; MOLECULAR EVOLUTION; NONHUMAN; PHYLOGENY; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN MOTIF; RURAL AREA; VIRUS GENE; VIRUS ISOLATION; VIRUS STRAIN; VIRUS TRANSMISSION; VIRUS VIRULENCE; EPIDEMIC; GENETIC VARIATION; GENETICS; GEOGRAPHY; INFLUENZA; PATHOGENICITY; TRANSMISSION; VIROLOGY; VIRUS GENOME;

CHINA; DISEASE OUTBREAKS; EVOLUTION, MOLECULAR; GENETIC VARIATION; GENOME, VIRAL; GEOGRAPHY; HEMAGGLUTININ GLYCOPROTEINS, INFLUENZA VIRUS; HUMANS; INFLUENZA A VIRUS, H7N9 SUBTYPE; INFLUENZA, HUMAN; NEURAMINIDASE; REASSORTANT VIRUSES;

EID: 85046902025     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.00301-18     Document Type: Article

References (53)

1. Belser JA, Bridges CB, Katz JM, Tumpey TM. 2009. Past, present, and possible future human infection with influenza virus A subtype H7. Emerg Infect Dis 15:859-865. https://doi.org/10.3201/eid1506.090072
2. Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, Chen J, Jie Z, Qiu H, Xu K, Xu X, Lu H, Zhu W, Gao Z, Xiang N, Shen Y, He Z, Gu Y, Zhang Z, Yang Y, Zhao X, Zhou L, Li X, Zou S, Zhang Y, Yang L, Guo J, Dong J, Li Q, Dong L, Zhu Y, Bai T, Wang S, Hao P, Yang W, Han J, Yu H, Li D, Gao GF, Wu G, Wang Y, Yuan Z, Shu Y. 2013. Human infection with a novel avianorigin influenza A (H7N9) virus. N Engl J Med 368:1888-1897. https://doi.org/10.1056/NEJMoa1304459
3. Liu D, Shi W, Shi Y, Wang D, Xiao H, Li W, Bi Y, Wu Y, Li X, Yan J, Liu W, Zhao G, Yang W, Wang Y, Ma J, Shu Y, Lei F, Gao GF. 2013. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet 381: 1926-1932. https://doi.org/10.1016/S0140-6736(13)60938-1
4. Gao HN, Lu HZ, Cao B, Du B, Shang H, Gan JH, Lu SH, Yang YD, Fang Q, Shen YZ, Xi XM, Gu Q, Zhou XM, Qu HP, Yan Z, Li FM, Zhao W, Gao ZC, Wang GF, Ruan LX, Wang WH, Ye J, Cao HF, Li XW, Zhang WH, Fang XC, He J, Liang WF, Xie J, Zeng M, Wu XZ, Li J, Xia Q, Jin ZC, Chen Q, Tang C, Zhang ZY, Hou BM, Feng ZX, Sheng JF, Zhong NS, Li LJ. 2013. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 368:2277-2285. https://doi.org/10.1056/NEJMoa1305584
5. Cowling BJ, Jin L, Lau EH, Liao Q, Wu P, Jiang H, Tsang TK, Zheng J, Fang VJ, Chang Z, Ni MY, Zhang Q, Ip DK, Yu J, Li Y, Wang L, Tu W, Meng L, Wu JT, Luo H, Li Q, Shu Y, Li Z, Feng Z, Yang W, Wang Y, Leung GM, Yu H. 2013. Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. Lancet 382:129-137. https://doi.org/10.1016/S0140-6736(13)61171-X
6. Liu J, Xiao H, Wu Y, Liu D, Qi X, Shi Y, Gao GF. 2014. H7N9: a low pathogenic avian influenza A virus infecting humans. Curr Opin Virol 5:91-97. https://doi.org/10.1016/j.coviro.2014.03.001
7. Gao GF, Wu Y. 2013. Haunted with and hunting for viruses. Sci China Life Sci 56:675-677. https://doi.org/10.1007/s11427-013-4525-x
8. Shi Y, Zhang W, Wang F, Qi J, Wu Y, Song H, Gao F, Bi Y, Zhang Y, Fan Z, Qin C, Sun H, Liu J, Haywood J, Liu W, Gong W, Wang D, Shu Y, Wang Y, Yan J, Gao GF. 2013. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses. Science 342:243-247. https://doi.org/10.1126/science.1242917
9. Xiong X, Martin SR, Haire LF, Wharton SA, Daniels RS, Bennett MS, McCauley JW, Collins PJ, Walker PA, Skehel JJ, Gamblin SJ. 2013. Receptor binding by an H7N9 influenza virus from humans. Nature 499: 496-499. https://doi.org/10.1038/nature12372
10. Xu R, de Vries RP, Zhu X, Nycholat CM, McBride R, Yu W, Paulson JC, Wilson IA. 2013. Preferential recognition of avian-like receptors in human influenza A H7N9 viruses. Science 342:1230-1235. https://doi.org/10.1126/science.1243761
11. Yang H, Carney PJ, Chang JC, Villanueva JM, Stevens J. 2013. Structural analysis of the hemagglutinin from the recent 2013 H7N9 influenza virus. J Virol 87:12433-12446. https://doi.org/10.1128/JVI.01854-13
12. Song W, Wang P, Mok BW, Lau SY, Huang X, Wu WL, Zheng M, Wen X, Yang S, Chen Y, Li L, Yuen KY, Chen H. 2014. The K526R substitution in viral protein PB2 enhances the effects of E627K on influenza virus replication. Nat Commun 5:5509. https://doi.org/10.1038/ncomms6509
13. Mok CK, Lee HH, Lestra M, Nicholls JM, Chan MC, Sia SF, Zhu H, Poon LL, Guan Y, Peiris JS. 2014. Amino acid substitutions in polymerase basic protein 2 gene contribute to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts. J Virol 88:3568-3576. https://doi.org/10.1128/JVI.02740-13
14. Bi Y, Xie Q, Zhang S, Li Y, Xiao H, Jin T, Zheng W, Li J, Jia X, Sun L, Liu J, Qin C, Gao GF, Liu W. 2015. Assessment of the internal genes of influenza A (H7N9) virus contributing to high pathogenicity in mice. J Virol 89:2-13. https://doi.org/10.1128/JVI.02390-14
15. Gao GF. 2014. Influenza and the live poultry trade. Science 344:235. https://doi.org/10.1126/science.1254664
16. Li J, Yu X, Pu X, Xie L, Sun Y, Xiao H, Wang F, Din H, Wu Y, Liu D, Zhao G, Liu J, Pan J. 2013. Environmental connections of novel avian-origin H7N9 influenza virus infection and virus adaptation to the human. Sci China Life Sci 56:485-492. https://doi.org/10.1007/s11427-013-4491-3
17. Wang X, Jiang H, Wu P, Uyeki TM, Feng L, Lai S, Wang L, Huo X, Xu K, Chen E, He J, Kang M, Zhang R, Zhang J, Wu J, Hu S, Zhang H, Liu X, Fu W, Ou J, Wu S, Qin Y, Zhang Z, Shi Y, Artois J, Fang VJ, Zhu H, Guan Y, Gilbert M, Horby PW, Leung GM, Gao GF, Cowling BJ, Yu H. 2017. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis 17:822-832. https://doi.org/10.1016/S1473-3099(17)30323-7
18. Yu H, Wu JT, Cowling BJ, Liao Q, Fang VJ, Zhou S, Wu P, Zhou H, Lau EH, Guo D, Ni MY, Peng Z, Feng L, Jiang H, Luo H, Li Q, Feng Z, Wang Y, Yang W, Leung GM. 2014. Effect of closure of live poultry markets on poultry-toperson transmission of avian influenza A H7N9 virus: an ecological study. Lancet 383:541-548. https://doi.org/10.1016/S0140-6736(13)61904-2
19. Lin YP, Yang ZF, Liang Y, Li ZT, Bond HS, Chua H, Luo YS, Chen Y, Chen TT, Guan WD, Lai JCC, Siu YL, Pan SH, Peiris JSM, Cowling BJ, PunMok CK. 2016. Population seroprevalence of antibody to influenza A(H7N9) virus, Guangzhou, China. BMC Infect Dis 16:632. https://doi.org/10.1186/s12879-016-1983-3
20. Zhang F, Bi Y, Wang J, Wong G, Shi W, Hu F, Yang Y, Yang L, Deng X, Jiang S, He X, Liu Y, Yin C, Zhong N, Gao GF. 2017. Human infections with recently-emerging highly pathogenic H7N9 avian influenza virus in China. J Infect 75:71-75. https://doi.org/10.1016/j.jinf.2017.04.001
21. Qi W, Jia W, Liu D, Li J, Bi Y, Xie S, Li B, Hu T, Du Y, Xing L, Zhang J, Zhang F, Wei X, Eden JS, Li H, Tian H, Li W, Su G, Lao G, Xu C, Xu B, Liu W, Zhang G, Ren T, Holmes EC, Cui J, Shi W, Gao GF, Liao M. 15 January 2018. Emergence and adaptation of a novel highly pathogenic H7N9 influenza virus in birds and humans from a 2013 human-infecting low-pathogenic ancestor. J Virol https://doi.org/10.1128/JVI.00921-17
22. Wang D, Yang L, Zhu W, Zhang Y, Zou S, Bo H, Gao R, Dong J, Huang W, Guo J, Li Z, Zhao X, Li X, Xin L, Zhou J, Chen T, Dong L, Wei H, Liu L, Tang J, Lan Y, Yang J, Shu Y. 2016. Two outbreak sources of influenza A (H7N9) viruses have been established in China. J Virol 90:5561-5573. https://doi.org/10.1128/JVI.03173-15
23. Bi Y, Shi W, Chen J, Chen Q, Ma Z, Wong G, Tian W, Yin R, Fu G, Yang Y, Liu WJ, Quan C, Wang Q, He S, Li X, Xia Q, Wang L, Pan Z, Li L, Li H, Xu W, Luo Y, Zeng H, Dai L, Xiao H, Sharshov K, Shestopalov A, Shi Y, Yan J, Li X, Liu Y, Lei F, Liu W, Gao GF. 2017. CASCIRE surveillance network and work on avian influenza viruses. Sci China Life Sci 60:1386-1391. https://doi.org/10.1007/s11427-017-9251-2
24. Bi Y, Chen Q, Wang Q, Chen J, Jin T, Wong G, Quan C, Liu J, Wu J, Yin R, Zhao L, Li M, Ding Z, Zou R, Xu W, Li H, Wang H, Tian K, Fu G, Huang Y, Shestopalov A, Li S, Xu B, Yu H, Luo T, Lu L, Xu X, Luo Y, Liu Y, Shi W, Liu D, Gao GF. 2016. Genesis, evolution and prevalence of H5N6 avian influenza viruses in China. Cell Host Microbe 20:810-821. https://doi.org/10.1016/j.chom.2016.10.022
25. Meliopoulos VA, Karlsson EA, Kercher L, Cline T, Freiden P, Duan S, Vogel P, Webby RJ, Guan Y, Peiris M, Thomas PG, Schultz-Cherry S. 2014. Human H7N9 and H5N1 influenza viruses differ in induction of cytokines and tissue tropism. J Virol 88:12982-12991. https://doi.org/10.1128/JVI.01571-14
26. Yang L, Zhu W, Li X, Chen M, Wu J, Yu P, Qi S, Huang Y, Shi W, Dong J, Zhao X, Huang W, Li Z, Zeng X, Bo H, Chen T, Chen W, Liu J, Zhang Y, Liang Z, Shi W, Shu Y, Wang D. 1 December 2017. Genesis and spread of newly emerged highly pathogenic H7N9 avian viruses in mainland China. J Virol https://doi.org/10.1128/JVI.01277-17
27. Kawaoka Y, Webster RG. 1988. Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A 85:324-328
28. Zhang Y, Sun Y, Sun H, Pu J, Bi Y, Shi Y, Lu X, Li J, Zhu Q, Gao GF, Yang H, Liu J. 2012. A single amino acid at the hemagglutinin cleavage site contributes to the pathogenicity and neurovirulence of H5N1 influenza virus in mice. J Virol 86:6924-6931. https://doi.org/10.1128/JVI.07142-11
29. Lu X, Shi Y, Zhang W, Zhang Y, Qi J, Gao GF. 2013. Structure and receptor-binding properties of an airborne transmissible avian influenza A virus hemagglutinin H5 (VN1203mut). Protein Cell 4:502-511. https://doi.org/10.1007/s13238-013-3906-z
30. Shi J, Deng G, Kong H, Gu C, Ma S, Yin X, Zeng X, Cui P, Chen Y, Yang H. 2017. H7N9 virulent mutants detected in chickens in China pose an increased threat to humans. Cell Res 12:1409-1421. https://doi.org/10.1038/cr.2017.129
31. 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 74:6015-6020. https://doi.org/10.1128/JVI.74.13.6015-6020.2000
32. Xu R, Zhu X, McBride R, Nycholat CM, Yu W, Paulson JC, Wilson IA. 2012. Functional balance of the hemagglutinin and neuraminidase activities accompanies the emergence of the 2009 H1N1 influenza pandemic. J Virol 86:9221-9232. https://doi.org/10.1128/JVI.00697-12
33. Casalegno JS, Ferraris O, Escuret V, Bouscambert M, Bergeron C, Lines L, Excoffier T, Valette M, Frobert E, Pillet S, Pozzetto B, Lina B, Ottmann M. 2014. Functional balance between the hemagglutinin and neuraminidase of influenza A(H1N1)pdm09 HA D222 variants. PLoS One 9:e104009. https://doi.org/10.1371/journal.pone.0104009
34. Gen F, Yamada S, Kato K, Akashi H, Kawaoka Y, Horimoto T. 2013. Attenuation of an influenza A virus due to alteration of its hemagglutinin-neuraminidase functional balance in mice. Arch Virol 158:1003-1011. https://doi.org/10.1007/s00705-012-1577-3
35. Yen HL, Liang CH, Wu CY, Forrest HL, Ferguson A, Choy KT, Jones J, Wong DD, Cheung PP, Hsu CH, Li OT, Yuen KM, Chan RW, Poon LL, Chan MC, Nicholls JM, Krauss S, Wong CH, Guan Y, Webster RG, Webby RJ, Peiris M. 2011. Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. Proc Natl Acad Sci U S A 108:14264-14269. https://doi.org/10.1073/pnas.1111000108
36. Zhang W, Qi J, Shi Y, Li Q, Gao F, Sun Y, Lu X, Lu Q, Vavricka CJ, Liu D, Yan J, Gao GF. 2010. Crystal structure of the swine-origin A (H1N1)-2009 influenza A virus hemagglutinin (HA) reveals similar antigenicity to that of the 1918 pandemic virus. Protein Cell 1:459-467. https://doi.org/10.1007/s13238-010-0059-1
37. Cui LB, Liu D, Shi WF, Pan JC, Qi X, Li XB, Guo XL, Zhou MH, Li W, Li J, Haywood J, Xiao HX, Yu XF, Pu XY, Wu Y, Yu HY, Zhao KC, Zhu YF, Wu B, Jin T, Shi ZY, Tang FY, Zhu FC, Sun QL, Wu LH, Yang RF, Yan JH, Lei FM, Zhu BL, Liu WJ, Ma JC, Wang H, Gao GF. 2014. Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus. Nat Commun 5:3142. https://doi.org/10.1038/ncomms4142
38. Lam TT, Zhou B, Wang J, Chai Y, Shen Y, Chen X, Ma C, Hong W, Chen Y, Zhang Y, Duan L, Chen P, Jiang J, Li L, Poon LL, Webby RJ, Smith DK, Leung GM, Peiris JS, Holmes EC, Guan Y, Zhu H. 2015. Dissemination, divergence and establishment of H7N9 influenza viruses in China. Nature 522:102-105. https://doi.org/10.1038/nature14348
39. Wang D, Yang L, Gao R, Zhang X, Tan Y, Wu A, Zhu W, Zhou J, Zou S, Li X, Sun Y, Zhang Y, Liu Y, Liu T, Xiong Y, Xu J, Chen L, Weng Y, Qi X, Guo J, Dong J, Huang W, Dong L, Zhao X, Liu L, Lu J, Lan Y, Wei H, Xin L, Chen Y, Xu C, Chen T, Zhu Y, Jiang T, Feng Z, Yang W, Wang Y, Zhu H, Guan Y, Gao GF, Li D, Han J, Wang S, Wu G, Shu Y. 2014. Genetic tuning of the novel avian influenza A(H7N9) virus during interspecies transmission, China, 2013. Euro Surveill 19:20836. https://doi.org/10.2807/1560-7917.ES2014.19.25.20836
40. Wu Y, Bi Y, Vavricka CJ, Sun X, Zhang Y, Gao F, Zhao M, Xiao H, Qin C, He J, Liu W, Yan J, Qi J, Gao GF. 2013. Characterization of two distinct neuraminidases from avian-origin human-infecting H7N9 influenza viruses. Cell Res 23:1347-1355. https://doi.org/10.1038/cr.2013.144
41. Imai M, Watanabe T, Kiso M, Nakajima N, Yamayoshi S, Iwatsuki-Horimoto K, Hatta M, Yamada S, Ito M, Sakai-Tagawa Y, Shirakura M, Takashita E, Fujisaki S, McBride R, Thompson AJ, Takahashi K, Maemura T, Mitake H, Chiba S, Zhong G, Fan S, Oishi K, Yasuhara A, Takada K, Nakao T, Fukuyama S, Yamashita M, Lopes TJS, Neumann G, Odagiri T, Watanabe S, Shu Y, Paulson JC, Hasegawa H, Kawaoka Y. 2017. A highly pathogenic avian H7N9 influenza virus isolated from a human is lethal in some ferrets infected via respiratory droplets. Cell Host Microbe 22: 615-626 e618. https://doi.org/10.1016/j.chom.2017.09.008
42. Xiao C, Ma W, Sun N, Huang L, Li Y, Zeng Z, Wen Y, Zhang Z, Li H, Li Q, Yu Y, Zheng Y, Liu S, Hu P, Zhang X, Ning Z, Qi W, Liao M. 2016. PB2-588 V promotes the mammalian adaptation of H10N8, H7N9 and H9N2 avian influenza viruses. Sci Rep 6:19474. https://doi.org/10.1038/srep19474
43. Naffakh N, Tomoiu A, Rameix-Welti MA, van der Werf S. 2008. Host restriction of avian influenza viruses at the level of the ribonucleoproteins. Annu Rev Microbiol 62:403-424. https://doi.org/10.1146/annurev.micro.62.081307.162746
44. Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, Huang JH, Shih YH, Wang JY, Chiang C, Chen CJ, Shih SR. 2006. Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis 12:1353-1360. https://doi.org/10.3201/eid1209.060276
45. Steinhauer DA. 1999. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258:1-20. https://doi.org/10.1006/viro.1999.9716
46. Jiao P, Tian G, Li Y, Deng G, Jiang Y, Liu C, Liu W, Bu Z, Kawaoka Y, Chen H. 2008. A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 82: 1146-1154. https://doi.org/10.1128/JVI.01698-07
47. Tada T, Suzuki K, Sakurai Y, Kubo M, Okada H, Itoh T, Tsukamoto K. 2011. Emergence of avian influenza viruses with enhanced transcription activity by a single amino acid substitution in the nucleoprotein during replication in chicken brains. J Virol 85:10354-10363. https://doi.org/10.1128/JVI.00605-11
48. Song MS, Pascua PN, Lee JH, Baek YH, Lee OJ, Kim CJ, Kim H, Webby RJ, Webster RG, Choi YK. 2009. The polymerase acidic protein gene of influenza a virus contributes to pathogenicity in a mouse model. J Virol 83:12325-12335. https://doi.org/10.1128/JVI.01373-09
49. Zamarin D, García-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:e4. https://doi.org/10.1371/journal.ppat.0010004
50. Ping J, Dankar SK, Forbes NE, Keleta L, Zhou Y, Tyler S, Brown EG. 2010. PB2 and hemagglutinin mutations are major determinants of host range and virulence in mouse-adapted influenza A virus. J Virol 84: 10606-10618. https://doi.org/10.1128/JVI.01187-10
51. Mok CK, Yen HL, Yu MY, Yuen KM, Sia SF, Chan MC, Qin G, Tu WW, Peiris JS. 2011. Amino acid residues 253 and 591 of the PB2 protein of avian influenza virus A H9N2 contribute to mammalian pathogenesis. J Virol 85:9641-9645. https://doi.org/10.1128/JVI.00702-11
52. Edgar RC. 2004. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792-1797. https://doi.org/10.1093/nar/gkh340
53. Stamatakis A. 2014. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30:1312-1313. https://doi.org/10.1093/bioinformatics/btu033