1887

Abstract

Although several studies have exploited the effects of PB1-F2 in swine influenza viruses, its contribution to the pathogenicity of swine influenza viruses remains unclear. Herein, we investigated the effects of PB1-F2 on the pathogenicity of influenza virus using a virulent H1N1 A/swine/Kansas/77778/2007 (KS07) virus, which expresses a full-length PB1-F2, in mice and pigs. Using reverse genetics, we generated the wild-type KS07 (KS07_WT), a PB1-F2 knockout mutant (KS07_K/O) and its N66S variant (KS07_N66S). KS07_K/O showed similar pathogenicity in mice to the KS07_WT, whereas KS07_N66S displayed enhanced virulence when compared to the other two viruses. KS07_WT exhibited more efficient replication in lungs and nasal shedding in infected pigs than the other two viruses. Pigs infected with the KS07_WT had higher pulmonary levels of granulocyte-macrophage colony-stimulating factor, IFN-γ, IL-6 and IL-8 at 3 and 5 days post-infection, as well as lower levels of IL-2, IL-4 and IL-12 at 1 day post-infection compared to those infected with the KS07_K/O. These results indicate that PB1-F2 modulates KS07 H1N1 virus replication, pathogenicity and innate immune responses in pigs and the single substitution at position 66 (N/S) in the PB1-F2 plays a critical role in virulence in mice. Taken together, our results provide new insights into the effects of PB1-F2 on the virulence of influenza virus in swine and support PB1-F2 as a virulence factor of influenza A virus in a strain- and host-dependent manner.

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2017-01-01
2024-11-12
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References

  1. Dowdle WR, Hattwick MA. Swine influenza virus infections in humans. J Infect Dis 1977; 136:S386–S389[PubMed] [CrossRef]
    [Google Scholar]
  2. Myers KP, Olsen CW, Gray GC. Cases of swine influenza in humans: a review of the literature. Clin Infect Dis 2007; 44:1084–1088 [View Article][PubMed]
    [Google Scholar]
  3. Peiris JS, Poon LL, Guan Y. Emergence of a novel swine-origin influenza A virus (S-OIV) H1N1 virus in humans. J Clin Virol 2009; 45:169–173 [View Article][PubMed]
    [Google Scholar]
  4. Shope RE. The etiology of swine influenza. Science 1931; 73:214–215 [View Article][PubMed]
    [Google Scholar]
  5. Zhou NN, Senne DA, Landgraf JS, Swenson SL, Erickson G et al. Emergence of H3N2 reassortant influenza A viruses in North American pigs. Vet Microbiol 2000; 74:47–58 [View Article][PubMed]
    [Google Scholar]
  6. Webby RJ, Swenson SL, Krauss SL, Gerrish PJ, Goyal SM et al. Evolution of swine H3N2 influenza viruses in the United States. J Virol 2000; 74:8243–8251 [View Article][PubMed]
    [Google Scholar]
  7. Karasin AI, Olsen CW, Anderson GA. Genetic characterization of an H1N2 influenza virus isolated from a pig in Indiana. J Clin Microbiol 2000; 38:2453–2456[PubMed]
    [Google Scholar]
  8. Webby RJ, Rossow K, Erickson G, Sims Y, Webster R. Multiple lineages of antigenically and genetically diverse influenza A virus co-circulate in the United States swine population. Virus Res 2004; 103:67–73 [View Article][PubMed]
    [Google Scholar]
  9. Lekcharoensuk P, Lager KM, Vemulapalli R, Woodruff M, Vincent AL et al. Novel swine influenza virus subtype H3N1, United States. Emerg Infect Dis 2006; 12:787–794 [View Article][PubMed]
    [Google Scholar]
  10. Vincent AL, Ma W, Lager KM, Janke BH, Richt JA. Swine influenza viruses: a North American perspective. Adv Virus Res 2008; 72:127–154 [View Article][PubMed]
    [Google Scholar]
  11. Ma W, Lager KM, Vincent AL, Janke BH, Gramer MR et al. The role of swine in the generation of novel influenza viruses. Zoonoses Public Health 2009; 56:326–337 [View Article][PubMed]
    [Google Scholar]
  12. Nelson MI, Stratton J, Killian ML, Janas-Martindale A, Vincent AL. Continual reintroduction of human pandemic H1N1 influenza A viruses into swine in the United States, 2009 to 2014. J Virol 2015; 89:6218–6226 [View Article][PubMed]
    [Google Scholar]
  13. Nelson MI, Vincent AL, Kitikoon P, Holmes EC, Gramer MR. Evolution of novel reassortant A/H3N2 influenza viruses in North American swine and humans, 2009–2011. J Virol 2012; 86:8872–8878 [View Article][PubMed]
    [Google Scholar]
  14. Chen W, Calvo PA, Malide D, Gibbs J, Schubert U et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 2001; 7:1306–1312 [View Article][PubMed]
    [Google Scholar]
  15. Lowy RJ. Influenza virus induction of apoptosis by intrinsic and extrinsic mechanisms. Int Rev Immunol 2003; 22:425–449[PubMed] [CrossRef]
    [Google Scholar]
  16. Zell R, Krumbholz A, Eitner A, Krieg R, Halbhuber KJ et al. Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 2007; 88:536–546 [View Article][PubMed]
    [Google Scholar]
  17. Pasricha G, Mishra AC, Chakrabarti AK. Comprehensive global amino acid sequence analysis of PB1F2 protein of influenza A H5N1 viruses and the influenza A virus subtypes responsible for the 20th-century pandemics. Influenza Other Respir Viruses 2013; 7:497–505 [View Article][PubMed]
    [Google Scholar]
  18. Pena L, Vincent AL, Loving CL, Henningson JN, Lager KM et al. Restored PB1-F2 in the 2009 pandemic H1N1 influenza virus has minimal effects in swine. J Virol 2012; 86:5523–5532 [View Article][PubMed]
    [Google Scholar]
  19. Schmolke M, Manicassamy B, Pena L, Sutton T, Hai R et al. 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 [View Article][PubMed]
    [Google Scholar]
  20. Leymarie O, Embury-Hyatt C, Chevalier C, Jouneau L, Moroldo M et al. PB1-F2 attenuates virulence of highly pathogenic avian H5N1 influenza virus in chickens. PLoS One 2014; 9:e100679 [View Article][PubMed]
    [Google Scholar]
  21. Deventhiran J, Kumar SR, 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 [View Article][PubMed]
    [Google Scholar]
  22. Pena L, Vincent AL, Loving CL, Henningson JN, Lager KM et al. Strain-dependent effects of PB1-F2 of triple-reassortant H3N2 influenza viruses in swine. J Gen Virol 2012; 93:2204–2214 [View Article][PubMed]
    [Google Scholar]
  23. Zamarin D, Ortigoza MB, Palese P. Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 2006; 80:7976–7983 [View Article][PubMed]
    [Google Scholar]
  24. Conenello GM, Zamarin D, Perrone LA, 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 [View Article][PubMed]
    [Google Scholar]
  25. Ma W, Belisle SE, Mosier D, Li X, Stigger-Rosser E et al. 2009 pandemic H1N1 influenza virus causes disease and upregulation of genes related to inflammatory and immune responses, cell death, and lipid metabolism in pigs. J Virol 2011; 85:11626–11637 [View Article][PubMed]
    [Google Scholar]
  26. Zamarin D, García-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 [View Article][PubMed]
    [Google Scholar]
  27. Chen CJ, Chen GW, Wang CH, Huang CH, Wang YC et al. Differential localization and function of PB1-F2 derived from different strains of influenza A virus. J Virol 2010; 84:10051–10062 [View Article][PubMed]
    [Google Scholar]
  28. Mazur I, Anhlan D, Mitzner D, Wixler L, Schubert U et al. The proapoptotic influenza A virus protein PB1-F2 regulates viral polymerase activity by interaction with the PB1 protein. Cell Microbiol 2008; 10:1140–1152 [View Article][PubMed]
    [Google Scholar]
  29. McAuley JL, Zhang K, Mccullers JA. 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 [View Article][PubMed]
    [Google Scholar]
  30. Le Goffic R, Bouguyon E, Chevalier C, Vidic J, da Costa B et al. Influenza A virus protein PB1-F2 exacerbates IFN-β expression of human respiratory epithelial cells. J Immunol 2010; 185:4812–4823 [View Article][PubMed]
    [Google Scholar]
  31. McAuley JL, Hornung F, Boyd KL, Smith AM, Mckeon R et al. 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 [View Article][PubMed]
    [Google Scholar]
  32. Alymova IV, Samarasinghe A, Vogel P, Green AM, Weinlich R et al. 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 [View Article][PubMed]
    [Google Scholar]
  33. Buehler J, Navi D, Lorusso A, Vincent A, Lager K et al. 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 [View Article][PubMed]
    [Google Scholar]
  34. Ma W, Vincent AL, Lager KM, Janke BH, Henry SC et al. Identification and characterization of a highly virulent triple reassortant H1N1 swine influenza virus in the United States. Virus Genes 2010; 40:28–36 [View Article][PubMed]
    [Google Scholar]
  35. Hai R, Schmolke M, Varga ZT, Manicassamy B, Wang TT et al. PB1-F2 expression by the 2009 pandemic H1N1 influenza virus has minimal impact on virulence in animal models. J Virol 2010; 84:4442–4450 [View Article][PubMed]
    [Google Scholar]
  36. Varga ZT, 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 [View Article][PubMed]
    [Google Scholar]
  37. Conenello GM, Tisoncik JR, Rosenzweig E, Varga ZT, Palese P et al. 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 [View Article][PubMed]
    [Google Scholar]
  38. Alymova IV, Green AM, van de Velde N, Mcauley JL, Boyd KL et al. 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 [View Article][PubMed]
    [Google Scholar]
  39. Gibbs JS, Malide D, Hornung F, Bennink JR, Yewdell JW. 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[PubMed] [CrossRef]
    [Google Scholar]
  40. 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 [View Article][PubMed]
    [Google Scholar]
  41. Chanturiya AN, Basañez G, Schubert U, Henklein P, Yewdell JW et al. PB1-F2, an influenza A virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranes. J Virol 2004; 78:6304–6312 [View Article][PubMed]
    [Google Scholar]
  42. Yoshizumi T, Ichinohe T, Sasaki O, Otera H, Kawabata S et al. Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nat Commun 2014; 5:4713 [View Article][PubMed]
    [Google Scholar]
  43. Solbak SM, Sharma A, Bruns K, Röder R, Mitzner D et al. Influenza A virus protein PB1-F2 from different strains shows distinct structural signatures. Biochim Biophys Acta 2013; 1834:568–582 [View Article][PubMed]
    [Google Scholar]
  44. Hoffmann E, Stech J, Guan Y, Webster RG, Perez DR. Universal primer set for the full-length amplification of all influenza A viruses. Arch Virol 2001; 146:2275–2289[PubMed] [CrossRef]
    [Google Scholar]
  45. Hoffmann E, Neumann G, Kawaoka Y, Hobom G, Webster RG. A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci USA 2000; 97:6108–6113 [View Article][PubMed]
    [Google Scholar]
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