1887

Abstract

The PB1-F2 protein of the influenza A viruses (IAVs) can act as a virulence factor in mice. Its contribution to the virulence of IAV in swine, however, remains largely unexplored. In this study, we chose two genetically related H3N2 triple-reassortant IAVs to assess the impact of PB1-F2 in virus replication and virulence in pigs. Using reverse genetics, we disrupted the PB1-F2 ORF of A/swine/Wisconsin/14094/99 (H3N2) (Sw/99) and A/turkey/Ohio/313053/04 (H3N2) (Ty/04). Removing the PB1-F2 ORF led to increased expression of PB1-N40 in a strain-dependent manner. Ablation of the PB1-F2 ORF (or incorporation of the N66S mutation in the PB1-F2 ORF, Sw/99 N66S) affected the replication in porcine alveolar macrophages of only the Sw/99 KO (PB1-F2 knockout) and Sw/99 N66S variants. The Ty/04 KO strain showed decreased virus replication in swine respiratory explants, whereas no such effect was observed in Sw/99 KO, compared with the wild-type (WT) counterparts. In pigs, PB1-F2 did not affect virus shedding or viral load in the lungs for any of these strains. Upon necropsy, PB1-F2 had no effect on the lung pathology caused by Sw/99 variants. Interestingly, the Ty/04 KO-infected pigs showed significantly increased lung pathology at 3 days post-infection compared with pigs infected with the Ty/04 WT strain. In addition, the pulmonary levels of interleukin (IL)-6, IL-8 and gamma interferon were regulated differentially by the expression of PB1-F2. Taken together, these results indicate that PB1-F2 modulates virus replication, virulence and innate immune responses in pigs in a strain-dependent fashion.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.045005-0
2012-10-01
2020-07-12
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/10/2204.html?itemId=/content/journal/jgv/10.1099/vir.0.045005-0&mimeType=html&fmt=ahah

References

  1. Alymova I. V., Green A. M., van de Velde N., McAuley J. L., Boyd K. L., Ghoneim H., McCullers J. A. 2011; Immunopathogenic and anti-bacterial effects of the H3N2 influenza A virus PB1-F2 map to amino acid residues 62, 75, 79, and 82. J Virol 85:12324–12333 [CrossRef]
    [Google Scholar]
  2. Brockmeier S. L., Lager K. M., Grubman M. J., Brough D. E., Ettyreddy D., Sacco R. E., Gauger P. C., Loving C. L., Vorwald A. C. other authors 2009; Adenovirus-mediated expression of interferon-alpha delays viral replication and reduces disease signs in swine challenged with porcine reproductive and respiratory syndrome virus. Viral Immunol 22:173–180 [CrossRef][PubMed]
    [Google Scholar]
  3. Bruder D., Srikiatkhachorn A., Enelow R. I. 2006; Cellular immunity and lung injury in respiratory virus infection. Viral Immunol 19:147–155 [CrossRef][PubMed]
    [Google Scholar]
  4. Chen W., Calvo P. A., Malide D., Gibbs J., Schubert U., Bacik I., Basta S., O’Neill R., Schickli J. other authors 2001; A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7:1306–1312 [CrossRef][PubMed]
    [Google Scholar]
  5. Choi Y. K., Lee J. H., Erickson G., Goyal S. M., Joo H. S., Webster R. G., Webby R. J. 2004; H3N2 influenza virus transmission from swine to turkeys, United States. Emerg Infect Dis 10:2156–2160 [CrossRef][PubMed]
    [Google Scholar]
  6. Conenello G. M., Zamarin D., Perrone L. A., 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:e1414–e1421 [CrossRef][PubMed]
    [Google Scholar]
  7. Dudek S. E., Wixler L., Nordhoff C., Nordmann A., Anhlan D., Wixler V., Ludwig S. 2011; The influenza virus PB1-F2 protein has interferon-antagonistic activity. Biol Chem 392:1135–1144 [CrossRef]
    [Google Scholar]
  8. Fukuyama S., Kawaoka Y. 2011; The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol 23:481–486 [CrossRef][PubMed]
    [Google Scholar]
  9. Gauger P. C., Vincent A. L., Loving C. L., Lager K. M., Janke B. H., Kehrli M. E. Jr, Roth J. A. 2011; Enhanced pneumonia and disease in pigs vaccinated with an inactivated human-like (δ-cluster) H1N2 vaccine and challenged with pandemic 2009 H1N1 influenza virus. Vaccine 29:2712–2719 [CrossRef][PubMed]
    [Google Scholar]
  10. Graham M. B., Dalton D. K., Giltinan D., Braciale V. L., Stewart T. A., Braciale T. J. 1993; Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178:1725–1732 [CrossRef][PubMed]
    [Google Scholar]
  11. Gramer M. R., Lee J. H., Choi Y. K., Goyal S. M., Joo H. S. 2007; Serologic and genetic characterization of North American H3N2 swine influenza A viruses. Can J Vet Res 71:201–206[PubMed]
    [Google Scholar]
  12. Halbur P. G., Paul P. S., Frey M. L., Landgraf J., Eernisse K., Meng X. J., Lum M. A., Andrews J. J., Rathje J. A. 1995; Comparison of the pathogenicity of two US porcine reproductive and respiratory syndrome virus isolates with that of the Lelystad virus. Vet Pathol 32:648–660 [CrossRef][PubMed]
    [Google Scholar]
  13. Hoffmann E., Neumann G., Kawaoka Y., Hobom G., Webster R. G. 2000; A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A 97:6108–6113 [CrossRef][PubMed]
    [Google Scholar]
  14. Kim H. M., Lee Y. W., Lee K. J., Kim H. S., Cho S. W., van Rooijen N., Guan Y., Seo S. H. 2008; Alveolar macrophages are indispensable for controlling influenza viruses in lungs of pigs. J Virol 82:4265–4274 [CrossRef][PubMed]
    [Google Scholar]
  15. Koh Y. Y., Jung E., Koh J. Y., Kim J. Y., Yoo Y., Kim C. K. 2007; Bronchoalveolar cellularity and interleukin-8 levels in measles bronchiolitis obliterans. Chest 131:1454–1460 [CrossRef][PubMed]
    [Google Scholar]
  16. Kumar S. R., Deflube L., Biswas M., Shobana R., Elankumaran S. 2011; Genetic characterization of swine influenza viruses (H3N2) isolated from Minnesota in 2006–2007. Virus Genes 43:161–176 [CrossRef][PubMed]
    [Google Scholar]
  17. Lamb R. A., Takeda M. 2001; Death by influenza virus protein. Nat Med 7:1286–1288 [CrossRef][PubMed]
    [Google Scholar]
  18. Le Goffic R., Bouguyon E., Chevalier C., Vidic J., Da Costa B., Leymarie O., Bourdieu C., Decamps L., Dhorne-Pollet S., Delmas B. 2010; Influenza A virus protein PB1-F2 exacerbates IFN-β expression of human respiratory epithelial cells. J Immunol 185:4812–4823 [CrossRef][PubMed]
    [Google Scholar]
  19. Le Goffic R., Leymarie O., Chevalier C., Rebours E., Da Costa B., Vidic J., Descamps D., Sallenave J. M., Rauch M. other authors 2011; Transcriptomic analysis of host immune and cell death responses associated with the influenza A virus PB1-F2 protein. PLoS Pathog 7:e1002202 [CrossRef][PubMed]
    [Google Scholar]
  20. Loving C. L., Brockmeier S. L., Ma W., Richt J. A., Sacco R. E. 2006; Innate cytokine responses in porcine macrophage populations: evidence for differential recognition of double-stranded RNA. J Immunol 177:8432–8439[PubMed] [CrossRef]
    [Google Scholar]
  21. Marjuki H., Scholtissek C., Franks J., Negovetich N. J., Aldridge J. R., Salomon R., Finkelstein D., Webster R. G. 2010; Three amino acid changes in PB1-F2 of highly pathogenic H5N1 avian influenza virus affect pathogenicity in mallard ducks. Arch Virol 155:925–934 [CrossRef][PubMed]
    [Google Scholar]
  22. McAuley J. L., Hornung F., Boyd K. L., Smith A. M., McKeon R., Bennink J., Yewdell J. W., McCullers J. A. 2007; Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2:240–249 [CrossRef][PubMed]
    [Google Scholar]
  23. McAuley J. L., Chipuk J. E., Boyd K. L., Van De Velde N., Green D. R., McCullers J. A. 2010a; PB1-F2 proteins from H5N1 and 20th century pandemic influenza viruses cause immunopathology. PLoS Pathog 6:e1001014 [CrossRef][PubMed]
    [Google Scholar]
  24. McAuley J. L., Zhang K., McCullers J. A. 2010b; The effects of influenza A virus PB1-F2 protein on polymerase activity are strain specific and do not impact pathogenesis. J Virol 84:558–564 [CrossRef][PubMed]
    [Google Scholar]
  25. Nfon C., Berhane Y., Zhang S., Handel K., Labrecque O., Pasick J. 2011; Molecular and antigenic characterization of triple-reassortant H3N2 swine influenza viruses isolated from pigs, turkey and quail in Canada. Transbound Emerg Dis 58:394–401 [CrossRef][PubMed]
    [Google Scholar]
  26. Pena L., Vincent A. L., Ye J., Ciacci-Zanella J. R., Angel M., Lorusso A., Gauger P. C., Janke B. H., Loving C. L., Perez D. R. 2011; Modifications in the polymerase genes of a swine-like triple-reassortant influenza virus to generate live attenuated vaccines against 2009 pandemic H1N1 viruses. J Virol 85:456–469 [CrossRef][PubMed]
    [Google Scholar]
  27. Pena L., Vincent A. L., Loving C. L., Henningson J. N., Lager K. M., Lorusso A., Perez D. R. 2012; Restored PB1-F2 in the 2009 pandemic H1N1 influenza virus has minimal effects in swine. J Virol 86:5523–5532 [CrossRef][PubMed]
    [Google Scholar]
  28. Reading P. C., Miller J. L., Anders E. M. 2000; Involvement of the mannose receptor in infection of macrophages by influenza virus. J Virol 74:5190–5197 [CrossRef][PubMed]
    [Google Scholar]
  29. Reed L. J., Muench H. 1938; A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497
    [Google Scholar]
  30. Richt J. A., Lager K. M., Janke B. H., Woods R. D., Webster R. G., Webby R. J. 2003; Pathogenic and antigenic properties of phylogenetically distinct reassortant H3N2 swine influenza viruses cocirculating in the United States. J Clin Microbiol 41:3198–3205 [CrossRef][PubMed]
    [Google Scholar]
  31. Rodgers B. C., Mims C. A. 1982; Influenza virus replication in human alveolar macrophages. J Med Virol 9:177–184 [CrossRef][PubMed]
    [Google Scholar]
  32. Schmolke M., Manicassamy B., Pena L., Sutton T., Hai R., Varga Z. T., Hale B. G., Steel J., Pérez D. R., García-Sastre A. 2011; Differential contribution of PB1-F2 to the virulence of highly pathogenic H5N1 influenza A virus in mammalian and avian species. PLoS Pathog 7:e1002186 [CrossRef][PubMed]
    [Google Scholar]
  33. Seo S. H., Webby R., Webster R. G. 2004; No apoptotic deaths and different levels of inductions of inflammatory cytokines in alveolar macrophages infected with influenza viruses. Virology 329:270–279 [CrossRef][PubMed]
    [Google Scholar]
  34. Shope R. E. 1931; The etiology of swine influenza. Science 73:214–215 [CrossRef][PubMed]
    [Google Scholar]
  35. Smith A. M., Adler F. R., McAuley J. L., Gutenkunst R. N., Ribeiro R. M., McCullers J. A., Perelson A. S. 2011; Effect of 1918 PB1-F2 expression on influenza A virus infection kinetics. PLOS Comput Biol 7:e1001081 [CrossRef][PubMed]
    [Google Scholar]
  36. Tate M. D., Pickett D. L., van Rooijen N., Brooks A. G., Reading P. C. 2010; Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol 84:7569–7580 [CrossRef][PubMed]
    [Google Scholar]
  37. Tauber S., Ligertwood Y., Quigg-Nicol M., Dutia B. M., Elliott R. M. 2012; Behaviour of influenza A viruses differentially expressing segment 2 gene products in vitro and in vivo . J Gen Virol 93:840–849 [CrossRef][PubMed]
    [Google Scholar]
  38. Uetani K., Hiroi M., Meguro T., Ogawa H., Kamisako T., Ohmori Y., Erzurum S. C. 2008; Influenza A virus abrogates IFN-γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway. Eur J Immunol 38:1559–1573 [CrossRef][PubMed]
    [Google Scholar]
  39. Upham J. P., Pickett D., Irimura T., Anders E. M., Reading P. C. 2010; Macrophage receptors for influenza A virus: role of the macrophage galactose-type lectin and mannose receptor in viral entry. J Virol 84:3730–3737 [CrossRef][PubMed]
    [Google Scholar]
  40. Van Poucke S. G., Nicholls J. M., Nauwynck H. J., Van Reeth K. 2010; Replication of avian, human and swine influenza viruses in porcine respiratory explants and association with sialic acid distribution. Virol J 7:38 [CrossRef][PubMed]
    [Google Scholar]
  41. van Riel D., Leijten L. M., van der Eerden M., Hoogsteden H. C., Boven L. A., Lambrecht B. N., Osterhaus A. D., Kuiken T. 2011; Highly pathogenic avian influenza virus H5N1 infects alveolar macrophages without virus production or excessive TNF-alpha induction. PLoS Pathog 7:e1002099 [CrossRef][PubMed]
    [Google Scholar]
  42. Varga Z. T., Ramos I., Hai R., Schmolke M., García-Sastre A., Fernandez-Sesma A., Palese P. 2011; The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. PLoS Pathog 7:e1002067 [CrossRef][PubMed]
    [Google Scholar]
  43. Vincent L. L., Janke B. H., Paul P. S., Halbur P. G. 1997; A monoclonal-antibody-based immunohistochemical method for the detection of swine influenza virus in formalin-fixed, paraffin-embedded tissues. J Vet Diagn Invest 9:191–195 [CrossRef][PubMed]
    [Google Scholar]
  44. Vincent A. L., Ma W., Lager K. M., Janke B. H., Richt J. A. 2008; Swine influenza viruses: a North American perspective. Adv Virus Res 72:127–154 [CrossRef][PubMed]
    [Google Scholar]
  45. Vincent A. L., Lager K. M., Faaberg K. S., Harland M., Zanella E. L., Ciacci-Zanella J. R., Kehrli M. E. Jr, Janke B. H., Klimov A. 2010; Experimental inoculation of pigs with pandemic H1N1 2009 virus and HI cross-reactivity with contemporary swine influenza virus antisera. Influenza Other Respir Viruses 4:53–60 [CrossRef][PubMed]
    [Google Scholar]
  46. Webby R. J., Rossow K., Erickson G., Sims Y., Webster R. 2004; Multiple lineages of antigenically and genetically diverse influenza A virus co-circulate in the United States swine population. Virus Res 103:67–73 [CrossRef][PubMed]
    [Google Scholar]
  47. Wise H. M., Foeglein A., Sun J., Dalton R. M., Patel S., Howard W., Anderson E. C., Barclay W. S., Digard P. 2009; A complicated message: identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol 83:8021–8031 [CrossRef][PubMed]
    [Google Scholar]
  48. 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 [CrossRef][PubMed]
    [Google Scholar]
  49. Zamarin D., Ortigoza M. B., Palese P. 2006; Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol 80:7976–7983 [CrossRef][PubMed]
    [Google Scholar]
  50. Zell R., Krumbholz A., Eitner A., Krieg R., Halbhuber K. J., Wutzler P. 2007; Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 88:536–546 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.045005-0
Loading
/content/journal/jgv/10.1099/vir.0.045005-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error