Evolution and virulence of influenza A virus protein PB1-F2

International Journal of Molecular Sciences

Volumn 19, Issue 1, 2018, Pages

  Kamal, Ram P ^a,b   Alymova, Irina V ^b   York, Ian A ^b  

^a BATTELLE MEMORIAL INSTITUTE   (United States)

^b NATIONAL CENTER FOR IMMUNIZATION AND RESPIRATORY DISEASES   (United States)

Author keywords

Influenza; Pathogenesis; PB1 F2; Virulence

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; PB1 F2 PROTEIN; RNA POLYMERASE; TUMOR NECROSIS FACTOR; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 2; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 3; UNCLASSIFIED DRUG; VIRAL PROTEIN; PB1-F2 PROTEIN, INFLUENZA A VIRUS;

APOPTOSIS; CELL DEATH; CYTOKINE PRODUCTION; CYTOTOXICITY; ENZYME ACTIVITY; EVOLUTION; GENE EXPRESSION; IMMUNE RESPONSE; IMMUNOMODULATION; INFLAMMATION; INFLUENZA A VIRUS; INNATE IMMUNITY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; VIRUS MORPHOLOGY; VIRUS REPLICATION; VIRUS VIRULENCE; ALTERNATIVE RNA SPLICING; ANIMAL; BIRD; CHEMISTRY; DOG; GENE EXPRESSION REGULATION; GENETICS; HORSE; HOST PATHOGEN INTERACTION; HUMAN; IMMUNOLOGY; METABOLISM; MOLECULAR EVOLUTION; ORTHOMYXOVIRUS INFECTION; PATHOGENICITY; PATHOLOGY; PIG; PROTEIN SECONDARY STRUCTURE; VIROLOGY; VIRULENCE;

ALTERNATIVE SPLICING; ANIMALS; BIRDS; DOGS; EVOLUTION, MOLECULAR; GENE EXPRESSION REGULATION, VIRAL; HORSES; HOST-PATHOGEN INTERACTIONS; HUMANS; INFLUENZA A VIRUS; ORTHOMYXOVIRIDAE INFECTIONS; PROTEIN STRUCTURE, SECONDARY; SWINE; VIRAL PROTEINS; VIRULENCE; VIRUS REPLICATION;

EID: 85039900369     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms19010096     Document Type: Review

References (70)

1. Vasin, A.V.; Temkina, O.A.; Egorov, V.V.; Klotchenko, S.A.; Plotnikova, M.A.; Kiselev, O.I. Molecular mechanisms enhancing the proteome of influenza a viruses: An overview of recently discovered proteins. Virus Res. 2014, 185, 53–63. [CrossRef] [PubMed]
2. Xu, G.; Zhang, X.; Liu, Q.; Bing, G.; Hu, Z.; Sun, H.; Xiong, X.; Jiang, M.; He, Q.; Wang, Y., et al. PA-X protein contributes to virulence of triple-reassortant H1N2 influenza virus by suppressing early immune responses in swine. Virology 2017, 508, 45–53. [CrossRef] [PubMed]
3. Vidy, A.; Maisonnasse, P.; Da Costa, B.; Delmas, B.; Chevalier, C.; Le Goffic, R. The influenza virus protein PB1-F2 increases viral pathogenesis through neutrophil recruitment and nk cells inhibition. PLoS ONE 2016, 11, e0165361. [CrossRef] [PubMed]
4. Zamarin, D.; Ortigoza, M.B.; Palese, P. Influenza a virus PB1-F2 protein contributes to viral pathogenesis in mice. J. Virol. 2006, 80, 7976–7983. [CrossRef] [PubMed]
5. Chen, W.; Calvo, P.A.; Malide, D.; Gibbs, J.; Schubert, U.; Bacik, I.; Basta, S.; O’Neill, R.; Schickli, J.; Palese, P., et al. A novel influenza a virus mitochondrial protein that induces cell death. Nat. Med. 2001, 7, 1306–1312. [CrossRef] [PubMed]
6. Wise, H.M.; Foeglein, A.; Sun, J.; Dalton, R.M.; Patel, S.; Howard, W.; Anderson, E.C.; Barclay, W.S.; Digard, P. A complicated message: Identification of a novel PB1-related protein translated from influenza a virus segment 2 mRNA. J. Virol. 2009, 83, 8021–8031. [CrossRef] [PubMed]
7. Chen, C.J.; Chen, G.W.; Wang, C.H.; Huang, C.H.; Wang, Y.C.; Shih, S.R. Differential localization and function of PB1-F2 derived from different strains of influenza a virus. J. Virol. 2010, 84, 10051–10062. [CrossRef] [PubMed]
8. Deventhiran, J.; Kumar, S.R.; Raghunath, S.; Leroith, T.; Elankumaran, S. PB1-F2 protein does not impact the virulence of triple-reassortant H3N2 swine influenza virus in pigs but alters pathogenicity and transmission in turkeys. J. Virol. 2015, 90, 222–231. [CrossRef] [PubMed]
9. Hai, R.; Schmolke, M.; Varga, Z.T.; Manicassamy, B.; Wang, T.T.; Belser, J.A.; Pearce, M.B.; Garcia-Sastre, A.; Tumpey, T.M.; Palese, P. PB1-F2 expression by the 2009 pandemic H1N1 influenza virus has minimal impact on virulence in animal models. J. Virol. 2010, 84, 4442–4450. [CrossRef] [PubMed]
10. Leymarie, O.; Embury-Hyatt, C.; Chevalier, C.; Jouneau, L.; Moroldo, M.; Da Costa, B.; Berhane, Y.; Delmas, B.; Weingartl, H.M.; Le Goffic, R. PB1-F2 attenuates virulence of highly pathogenic avian H5N1 influenza virus in chickens. PLoS ONE 2014, 9, e100679. [CrossRef] [PubMed]
11. McAuley, J.L.; Chipuk, J.E.; Boyd, K.L.; Van De Velde, N.; Green, D.R.; McCullers, J.A. PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology. PLoS Pathog. 2010, 6, e1001014. [CrossRef] [PubMed]
12. Bruns, K.; Studtrucker, N.; Sharma, A.; Fossen, T.; Mitzner, D.; Eissmann, A.; Tessmer, U.; Roder, R.; Henklein, P.; Wray, V., et al. Structural characterization and oligomerization of PB1-F2, a proapoptotic influenza a virus protein. J. Biol. Chem. 2007, 282, 353–363. [CrossRef] [PubMed]
13. Chevalier, C.; Al Bazzal, A.; Vidic, J.; Fevrier, V.; Bourdieu, C.; Bouguyon, E.; Le Goffic, R.; Vautherot, J.F.; Bernard, J.; Moudjou, M., et al. PB1-F2 influenza a virus protein adopts a beta-sheet conformation and forms amyloid fibers in membrane environments. J. Biol. Chem. 2010, 285, 13233–13243. [CrossRef] [PubMed]
14. Gibbs, J.S.; Malide, D.; Hornung, F.; Bennink, J.R.; Yewdell, J.W. The influenza a virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J. Virol. 2003, 77, 7214–7224. [CrossRef] [PubMed]
15. Yamada, H.; Chounan, R.; Higashi, Y.; Kurihara, N.; Kido, H. Mitochondrial targeting sequence of the influenza a virus PB1-F2 protein and its function in mitochondria. FEBS Lett. 2004, 578, 331–336. [CrossRef] [PubMed]
16. Solbak, S.M.; Sharma, A.; Bruns, K.; Roder, R.; Mitzner, D.; Hahn, F.; Niebert, R.; Vedeler, A.; Henklein, P.; Henklein, P., et al. Influenza a virus protein PB1-F2 from different strains shows distinct structural signatures. Biochim. Biophys. Acta 2013, 1834, 568–582. [CrossRef] [PubMed]
17. Henkel, M.; Mitzner, D.; Henklein, P.; Meyer-Almes, F.J.; Moroni, A.; Difrancesco, M.L.; Henkes, L.M.; Kreim, M.; Kast, S.M.; Schubert, U., et al. The proapoptotic influenza a virus protein PB1-F2 forms a nonselective ion channel. PLoS ONE 2010, 5, e11112. [CrossRef] [PubMed]
18. Vidic, J.; Richard, C.A.; Pechoux, C.; Da Costa, B.; Bertho, N.; Mazerat, S.; Delmas, B.; Chevalier, C. Amyloid assemblies of influenza a virus pb1-f2 protein damage membrane and induce cytotoxicity. J. Biol. Chem. 2016, 291, 739–751. [CrossRef] [PubMed]
19. Kamal, R.P.; Kumar, A.; Davis, C.T.; Tzeng, W.P.; Nguyen, T.; Donis, R.O.; Katz, J.M.; York, I.A. Emergence of highly pathogenic avian influenza a(H5N1) virus PB1-F2 variants and their virulence in BALB/c mice. J. Virol. 2015, 89, 5835–5846. [CrossRef] [PubMed]
20. Zell, R.; Krumbholz, A.; Eitner, A.; Krieg, R.; Halbhuber, K.J.; Wutzler, P. Prevalence of PB1-F2 of influenza a viruses. J. Gen. Virol. 2007, 88, 536–546. [CrossRef] [PubMed]
21. Tauber, S.; Ligertwood, Y.; Quigg-Nicol, M.; Dutia, B.M.; Elliott, R.M. Behaviour of influenza a viruses differentially expressing segment 2 gene products in vitro and in vivo. J. Gen. Virol. 2012, 93, 840–849. [CrossRef] [PubMed]
22. Kosik, I.; Praznovska, M.; Kosikova, M.; Bobisova, Z.; Holly, J.; Vareckova, E.; Kostolansky, F.; Russ, G. The ubiquitination of the influenza a virus PB1-F2 protein is crucial for its biological function. PLoS ONE 2015, 10, e0118477. [CrossRef] [PubMed]
23. Buehler, J.; Navi, D.; Lorusso, A.; Vincent, A.; Lager, K.; Miller, C.L. Influenza a virus PB1-F2 protein expression is regulated in a strain-specific manner by sequences located downstream of the PB1-F2 initiation codon. J. Virol. 2013, 87, 10687–10699. [CrossRef] [PubMed]
24. Alymova, I.V.; Samarasinghe, A.; Vogel, P.; Green, A.M.; Weinlich, R.; McCullers, J.A. A novel cytotoxic sequence contributes to influenza a viral protein PB1-F2 pathogenicity and predisposition to secondary bacterial infection. J. Virol. 2014, 88, 503–515. [CrossRef] [PubMed]
25. Schmolke, M.; Manicassamy, B.; Pena, L.; Sutton, T.; Hai, R.; Varga, Z.T.; Hale, B.G.; Steel, J.; Perez, D.R.; Garcia-Sastre, A. Differential contribution of PB1-F2 to the virulence of highly pathogenic H5N1 influenza a virus in mammalian and avian species. PLoS Pathog. 2011, 7, e1002186. [CrossRef] [PubMed]
26. Mazur, I.; Anhlan, D.; Mitzner, D.; Wixler, L.; Schubert, U.; Ludwig, S. The proapoptotic influenza a virus protein PB1-F2 regulates viral polymerase activity by interaction with the pb1 protein. Cell. Microbiol. 2008, 10, 1140–1152. [CrossRef] [PubMed]
27. Misawa, T.; Takahama, M.; Saitoh, T. Mitochondria-endoplasmic reticulum contact sites mediate innate immune responses. Adv. Exp. Med. Biol. 2017, 997, 187–197. [PubMed]
28. West, A.P.; Shadel, G.S.; Ghosh, S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 2011, 11, 389–402. [CrossRef] [PubMed]
29. Takeuchi, O.; Akira, S. Innate immunity to virus infection. Immunol. Rev. 2009, 227, 75–86. [CrossRef] [PubMed]
30. Subramanian, N.; Natarajan, K.; Clatworthy, M.R.; Wang, Z.; Germain, R.N. The adaptor mavs promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 2013, 153, 348–361. [CrossRef] [PubMed]
31. Varga, Z.T.; Ramos, I.; Hai, R.; Schmolke, M.; Garcia-Sastre, A.; Fernandez-Sesma, A.; Palese, P. The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the mavs adaptor protein. PLoS Pathog. 2011, 7, e1002067. [CrossRef] [PubMed]
32. Varga, Z.T.; Grant, A.; Manicassamy, B.; Palese, P. Influenza virus protein PB1-F2 inhibits the induction of type I interferon by binding to mavs and decreasing mitochondrial membrane potential. J. Virol. 2012, 86, 8359–8366. [CrossRef] [PubMed]
33. Yoshizumi, T.; Ichinohe, T.; Sasaki, O.; Otera, H.; Kawabata, S.; Mihara, K.; Koshiba, T. Influenza a virus protein PB1-F2 translocates into mitochondria via tom40 channels and impairs innate immunity. Nat. Commun. 2014, 5, 4713. [CrossRef] [PubMed]
34. Le Goffic, R.; Bouguyon, E.; Chevalier, C.; Vidic, J.; Da Costa, B.; Leymarie, O.; Bourdieu, C.; Decamps, L.; Dhorne-Pollet, S.; Delmas, B. Influenza a virus protein PB1-F2 exacerbates ifn-beta expression of human respiratory epithelial cells. J. Immunol. 2010, 185, 4812–4823. [CrossRef] [PubMed]
35. Le Goffic, R.; Leymarie, O.; Chevalier, C.; Rebours, E.; Da Costa, B.; Vidic, J.; Descamps, D.; Sallenave, J.M.; Rauch, M.; Samson, M., et al. Transcriptomic analysis of host immune and cell death responses associated with the influenza a virus PB1-F2 protein. PLoS Pathog. 2011, 7, e1002202. [CrossRef] [PubMed]
36. Leymarie, O.; Meyer, L.; Tafforeau, L.; Lotteau, V.; Costa, B.D.; Delmas, B.; Chevalier, C.; Le Goffic, R. Influenza virus protein PB1-F2 interacts with CALCOCO2 (NDP52) to modulate innate immune response. J. Gen. Virol. 2017, 98, 1196–1208. [CrossRef] [PubMed]
37. Jaworska, J.; Coulombe, F.; Downey, J.; Tzelepis, F.; Shalaby, K.; Tattoli, I.; Berube, J.; Rousseau, S.; Martin, J.G.; Girardin, S.E., et al. NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein. Proc. Natl. Acad. Sci. USA 2014, 111, E2110–E2119. [CrossRef] [PubMed]
38. Dudek, S.E.; Wixler, L.; Nordhoff, C.; Nordmann, A.; Anhlan, D.; Wixler, V.; Ludwig, S. The influenza virus PB1-F2 protein has interferon antagonistic activity. Biol. Chem. 2011, 392, 1135–1144. [CrossRef] [PubMed]
39. Meunier, I.; von Messling, V. PB1-F2 modulates early host responses but does not affect the pathogenesis of H1N1 seasonal influenza virus. J. Virol. 2012, 86, 4271–4278. [CrossRef] [PubMed]
40. McAuley, J.L.; Tate, M.D.; MacKenzie-Kludas, C.J.; Pinar, A.; Zeng, W.; Stutz, A.; Latz, E.; Brown, L.E.; Mansell, A. Activation of the NLRP3 inflammasome by iav virulence protein PB1-F2 contributes to severe pathophysiology and disease. PLoS Pathog. 2013, 9, e1003392. [CrossRef] [PubMed]
41. Pena, L.; Vincent, A.L.; Loving, C.L.; Henningson, J.N.; Lager, K.M.; Li, W.; Perez, D.R. Strain-dependent effects of PB1-F2 of triple-reassortant H3N2 influenza viruses in swine. J. Gen. Virol. 2012, 93, 2204–2214. [CrossRef] [PubMed]
42. Lee, J.; Henningson, J.; Ma, J.; Duff, M.; Lang, Y.; Li, Y.; Li, Y.; Nagy, A.; Sunwoo, S.; Bawa, B., et al. Effects of PB1-F2 on the pathogenicity of H1N1 swine influenza virus in mice and pigs. J. Gen. Virol. 2017. [CrossRef] [PubMed]
43. Reis, A.L.; McCauley, J.W. The influenza virus protein PB1-F2 interacts with ikkbeta and modulates NF-kappab signalling. PLoS ONE 2013, 8, e63852. [CrossRef] [PubMed]
44. Pinar, A.; Dowling, J.K.; Bitto, N.J.; Robertson, A.A.; Latz, E.; Stewart, C.R.; Drummond, G.R.; Cooper, M.A.; McAuley, J.L.; Tate, M.D., et al. PB1-F2 peptide derived from avian influenza a virus H7N9 induces inflammation via activation of the NLRP3 inflammasome. J. Biol. Chem. 2017, 292, 826–836. [CrossRef] [PubMed]
45. Kosik, I.; Krejnusova, I.; Bystricka, M.; Polakova, K.; Russ, G. N-terminal region of the PB1-F2 protein is responsible for increased expression of influenza a viral protein PB1. Acta Virol. 2011, 55, 45–53. [CrossRef] [PubMed]
46. Ozawa, M.; Basnet, S.; Burley, L.M.; Neumann, G.; Hatta, M.; Kawaoka, Y. Impact of amino acid mutations in PB2, PB1-F2, and NS1 on the replication and pathogenicity of pandemic (H1N1) 2009 influenza viruses. J. Virol. 2011, 85, 4596–4601. [CrossRef] [PubMed]
47. McAuley, J.L.; Zhang, K.; McCullers, J.A. The effects of influenza a virus PB1-F2 protein on polymerase activity are strain specific and do not impact pathogenesis. J. Virol. 2010, 84, 558–564. [CrossRef] [PubMed]
48. Leymarie, O.; Jouvion, G.; Herve, P.L.; Chevalier, C.; Lorin, V.; Lecardonnel, J.; Da Costa, B.; Delmas, B.; Escriou, N.; Le Goffic, R. Kinetic characterization of PB1-F2-mediated immunopathology during highly pathogenic avian H5N1 influenza virus infection. PLoS ONE 2013, 8, e57894. [CrossRef] [PubMed]
49. Cheng, Y.Y.; Yang, S.R.; Wang, Y.T.; Lin, Y.H.; Chen, C.J. Amino acid residues 68–71 contribute to influenza a virus PB1-F2 protein stability and functions. Front. Microbiol. 2017, 8, 692. [CrossRef] [PubMed]
50. Iverson, A.R.; Boyd, K.L.; McAuley, J.L.; Plano, L.R.; Hart, M.E.; McCullers, J.A. Influenza virus primes mice for pneumonia from staphylococcus aureus. J. Infect. Dis. 2011, 203, 880–888. [CrossRef] [PubMed]
51. Mitzner, D.; Dudek, S.E.; Studtrucker, N.; Anhlan, D.; Mazur, I.; Wissing, J.; Jansch, L.; Wixler, L.; Bruns, K.; Sharma, A., et al. Phosphorylation of the influenza a virus protein PB1-F2 by PKC is crucial for apoptosis promoting functions in monocytes. Cell. Microbiol. 2009, 11, 1502–1516. [CrossRef] [PubMed]
52. Chanturiya, A.N.; Basanez, G.; Schubert, U.; Henklein, P.; Yewdell, J.W.; Zimmerberg, J. PB1-F2, an influenza a virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranes. J. Virol. 2004, 78, 6304–6312. [CrossRef] [PubMed]
53. Zamarin, D.; Garcia-Sastre, A.; Xiao, X.; Wang, R.; Palese, P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 2005, 1, e4. [CrossRef] [PubMed]
54. Takahashi, T.; Takaguchi, M.; Kawakami, T.; Suzuki, T. Sulfatide regulates caspase-3-independent apoptosis of influenza a virus through viral PB1-F2 protein. PLoS ONE 2013, 8, e61092. [CrossRef] [PubMed]
55. McAuley, J.L.; Hornung, F.; Boyd, K.L.; Smith, A.M.; McKeon, R.; Bennink, J.; Yewdell, J.W.; McCullers, J.A. Expression of the 1918 influenza a virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2007, 2, 240–249. [CrossRef] [PubMed]
56. Pena, L.; Vincent, A.L.; Loving, C.L.; Henningson, J.N.; Lager, K.M.; Lorusso, A.; Perez, D.R. Restored PB1-F2 in the 2009 pandemic H1N1 influenza virus has minimal effects in swine. J. Virol. 2012, 86, 5523–5532. [CrossRef] [PubMed]
57. James, J.; Howard, W.; Iqbal, M.; Nair, V.K.; Barclay, W.S.; Shelton, H. Influenza a virus PB1-F2 protein prolongs viral shedding in chickens lengthening the transmission window. J. Gen. Virol. 2016, 97, 2516–2527. [CrossRef] [PubMed]
58. Alymova, I.V.; Green, A.M.; van de Velde, N.; McAuley, J.L.; Boyd, K.L.; Ghoneim, H.E.; McCullers, J.A. Immunopathogenic and antibacterial effects of H3N2 influenza a virus PB1-F2 map to amino acid residues 62, 75, 79, and 82. J. Virol. 2011, 85, 12324–12333. [CrossRef] [PubMed]
59. Alymova, I.V.; McCullers, J.A.; Kamal, R.P.; Vogel, P.; Green, A.M.; Ganesbom, S.; York, I.A. Dynamics of virulent PB1-F2 residues in human influenza a virus isolates and viral fitness in mice. Unpublished work, 2017.
60. Conenello, G.M.; Zamarin, D.; Perrone, L.A.; Tumpey, T.; Palese, P. A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza a viruses contributes to increased virulence. PLoS Pathog. 2007, 3, 1414–1421. [CrossRef] [PubMed]
61. Conenello, G.M.; Tisoncik, J.R.; Rosenzweig, E.; Varga, Z.T.; Palese, P.; Katze, M.G. A single n66s mutation in the PB1-F2 protein of influenza a virus increases virulence by inhibiting the early interferon response in vivo. J. Virol. 2011, 85, 652–662. [CrossRef] [PubMed]
62. Weeks-Gorospe, J.N.; Hurtig, H.R.; Iverson, A.R.; Schuneman, M.J.; Webby, R.J.; McCullers, J.A.; Huber, V.C. Naturally occurring swine influenza a virus PB1-F2 phenotypes that contribute to superinfection with gram-positive respiratory pathogens. J. Virol. 2012, 86, 9035–9043. [CrossRef] [PubMed]
63. McAuley, J.; Deng, Y.M.; Gilbertson, B.; Mackenzie-Kludas, C.; Barr, I.; Brown, L. Rapid evolution of the PB1-F2 virulence protein expressed by human seasonal H3N2 influenza viruses reduces inflammatory responses to infection. Virol. J. 2017, 14, 162. [CrossRef] [PubMed]
64. Marjuki, H.; Scholtissek, C.; Franks, J.; Negovetich, N.J.; Aldridge, J.R.; Salomon, R.; Finkelstein, D.; Webster, R.G. Three amino acid changes in PB1-F2 of highly pathogenic H5N1 avian influenza virus affect pathogenicity in mallard ducks. Arch. Virol. 2010, 155, 925–934. [CrossRef] [PubMed]
65. Chang, P.; Kuchipudi, S.V.; Mellits, K.H.; Sebastian, S.; James, J.; Liu, J.; Shelton, H.; Chang, K.C. Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation. Sci. Rep. 2015, 5, 17999. [CrossRef] [PubMed]
66. Betakova, T.; Kostrabova, A.; Lachova, V.; Turianova, L. Cytokines induced during influenza virus infection. Curr. Pharm. Des. 2017, 23, 2616–2622. [CrossRef] [PubMed]
67. McClain, M.T.; Henao, R.; Williams, J.; Nicholson, B.; Veldman, T.; Hudson, L.; Tsalik, E.L.; Lambkin-Williams, R.; Gilbert, A.; Mann, A., et al. Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge. Clin. Exp. Immunol. 2016, 183, 441–451. [CrossRef] [PubMed]
68. Alymova, I.V.; York, I.A.; McCullers, J.A. Non-avian animal reservoirs present a source of influenza a PB1-F2 proteins with novel virulence-enhancing markers. PLoS ONE 2014, 9, e111603. [CrossRef] [PubMed]
69. Worobey, M.; Han, G.Z.; Rambaut, A. A synchronized global sweep of the internal genes of modern avian influenza virus. Nature 2014, 508, 254–257. [CrossRef] [PubMed]
70. Kawaoka, Y.; Krauss, S.; Webster, R.G. Avian-to-human transmission of the PB1 gene of influenza a viruses in the 1957 and 1968 pandemics. J. Virol. 1989, 63, 4603–4608. [PubMed]