1887

Abstract

Influenza A virus has caused a number of pandemics in past decades, including the recent H1N1-2009 pandemic. Viperin is an interferon (IFN)-inducible protein of innate immunity, and acts as a broad-spectrum antiviral protein. We explored the antiviral activities and mechanisms of viperin during influenza virus (IFV) infection and . Wild-type (WT) HeLa and viperin-expressing HeLa cells were infected with influenza A/WSN/33/H1N1 (WSN33) virus, and subjected to virological, light and electron microscopic analyses. Viperin expression reduced virus replication and titres, and restricted viral budding. Young and old viperin-knockout (KO) mice and WT control animals were challenged with influenza WSN33 at lethal doses of 10 and 10 p.f.u. via the intratracheal route. Lungs were subjected to histopathological, virological and molecular studies. Upon lethal IFV challenge, both WT and KO mice revealed similar trends of infection and recovery with similar mortality rates. Viral quantification assay and histopathological evaluation of lungs from different time points showed no significant difference in viral loads and lung damage scores between the two groups of mice. Although the studies demonstrated the ability of viperin to restrict influenza H1N1 virus replication, the viperin-deficient mouse model indicated that absence of viperin enhanced neither the viral load nor pulmonary damage in the lungs of infected mice. This may be due to the compensation of IFN-stimulated genes in the lungs and/or the influenza non-structural protein 1-mediated IFN antagonism dampening the IFN response, thereby rendering the loss of viperin insignificant. Nevertheless, further investigations that exploit the antiviral mechanisms of viperin as prophylaxis are still warranted.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.040824-0
2012-06-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/6/1269.html?itemId=/content/journal/jgv/10.1099/vir.0.040824-0&mimeType=html&fmt=ahah

References

  1. Boudinot P., Riffault S., Salhi S., Carrat C., Sedlik C., Mahmoudi N., Charley B., Benmansour A. 2000; Vesicular stomatitis virus and pseudorabies virus induce a vig1/cig5 homologue in mouse dendritic cells via different pathways. J Gen Virol 81:2675–2682[PubMed]
    [Google Scholar]
  2. Chin K. C., Cresswell P. 2001; Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proc Natl Acad Sci U S A 98:15125–15130 [View Article][PubMed]
    [Google Scholar]
  3. de Wit E., Fouchier R. A. M. 2008; Emerging influenza. J Clin Virol 41:1–6 [View Article][PubMed]
    [Google Scholar]
  4. Fitzgerald K. A. 2011; The interferon inducible gene: viperin. J Interferon Cytokine Res 31:131–135 [View Article][PubMed]
    [Google Scholar]
  5. Hale B. G., Albrecht R. A., García-Sastre A. 2010; Innate immune evasion strategies of influenza viruses. Future Microbiol 5:23–41 [View Article][PubMed]
    [Google Scholar]
  6. Helbig K. J., Lau D. T., Semendric L., Harley H. A., Beard M. R. 2005; Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector. Hepatology 42:702–710 [View Article][PubMed]
    [Google Scholar]
  7. Hinson E. R., Cresswell P. 2009; The antiviral protein, viperin, localizes to lipid droplets via its N-terminal amphipathic α-helix. Proc Natl Acad Sci U S A 106:20452–20457 [View Article][PubMed]
    [Google Scholar]
  8. Jiang D., Guo H., Xu C., Chang J., Gu B., Wang L., Block T. M., Guo J. T. 2008; Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol 82:1665–1678 [View Article][PubMed]
    [Google Scholar]
  9. Karlas A., Machuy N., Shin Y., Pleissner K. P., Artarini A., Heuer D., Becker D., Khalil H., Ogilvie L. A. other authors 2010; Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463:818–822 [View Article][PubMed]
    [Google Scholar]
  10. Kaushik D. K., Gupta M., Basu A. 2011; Microglial response to viral challenges: every silver lining comes with a cloud. Front Biosci 17:2187–2205[PubMed] [CrossRef]
    [Google Scholar]
  11. König R., Stertz S., Zhou Y., Inoue A., Hoffmann H. H., Bhattacharyya S., Alamares J. G., Tscherne D. M., Ortigoza M. B. other authors 2010; Human host factors required for influenza virus replication. Nature 463:813–817 [View Article][PubMed]
    [Google Scholar]
  12. Lee V. J., Tay J. K., Chen M. I., Phoon M. C., Xie M. L., Wu Y., Lee C. X., Yap J., Sakharkar K. R. other authors 2010; Inactivated trivalent seasonal influenza vaccine induces limited cross-reactive neutralizing antibody responses against 2009 pandemic and 1934 PR8 H1N1 strains. Vaccine 28:6852–6857 [View Article][PubMed]
    [Google Scholar]
  13. Leong W. F., Chow V. T. 2006; Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal differential cellular gene expression in response to enterovirus 71 infection. Cell Microbiol 8:565–580 [View Article][PubMed]
    [Google Scholar]
  14. Lim S. M., Koraka P., Osterhaus A. D., Martina B. E. 2011; West Nile virus: immunity and pathogenesis. Viruses 3:811–828 [View Article][PubMed]
    [Google Scholar]
  15. Matute-Bello G., Winn R. K., Jonas M., Chi E. Y., Martin T. R., Liles W. C. 2001; Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation. Am J Pathol 158:153–161 [View Article][PubMed]
    [Google Scholar]
  16. Memoli M. J., Morens D. M., Taubenberger J. K. 2008; Pandemic and seasonal influenza: therapeutic challenges. Drug Discov Today 13:590–595 [View Article][PubMed]
    [Google Scholar]
  17. Moltedo B., López C. B., Pazos M., Becker M. I., Hermesh T., Moran T. M. 2009; Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity. J Immunol 183:3569–3573 [View Article][PubMed]
    [Google Scholar]
  18. Narasaraju T., Yang E., Samy R. P., Ng H. H., Poh W. P., Liew A. A., Phoon M. C., van Rooijen N., Chow V. T. 2011; Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol 179:199–210 [View Article][PubMed]
    [Google Scholar]
  19. Nayak D. P., Balogun R. A., Yamada H., Zhou Z. H., Barman S. 2009; Influenza virus morphogenesis and budding. Virus Res 143:147–161 [View Article][PubMed]
    [Google Scholar]
  20. Ono A., Freed E. O. 2005; Role of lipid rafts in virus replication. Adv Virus Res 64:311–358 [View Article][PubMed]
    [Google Scholar]
  21. Patrozou E., Mermel L. A. 2009; Does influenza transmission occur from asymptomatic infection or prior to symptom onset?. Public Health Rep 124:193–196[PubMed]
    [Google Scholar]
  22. Phoon M. C., Desbordes C., Howe J., Chow V. T. 2001; Linoleic and linolelaidic acids differentially influence proliferation and apoptosis of MOLT-4 leukaemia cells. Cell Biol Int 25:777–784 [View Article][PubMed]
    [Google Scholar]
  23. Qiu L. Q., Cresswell P., Chin K. C. 2009; Viperin is required for optimal Th2 responses and T-cell receptor-mediated activation of NF-κB and AP-1. Blood 113:3520–3529 [View Article][PubMed]
    [Google Scholar]
  24. Reilly J. F., Martinez S. D., Mickey G., Maher P. A. 2002; A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor-mediated signal transduction. Biochem J 366:501–510 [View Article][PubMed]
    [Google Scholar]
  25. Saitoh T., Satoh T., Yamamoto N., Uematsu S., Takeuchi O., Kawai T., Akira S. 2011; Antiviral protein viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity 34:352–363 [View Article][PubMed]
    [Google Scholar]
  26. Sanders C. J., Doherty P. C., Thomas P. G. 2011; Respiratory epithelial cells in innate immunity to influenza virus infection. Cell Tissue Res 343:13–21 [View Article][PubMed]
    [Google Scholar]
  27. Schmolke M., García-Sastre A. 2010; Evasion of innate and adaptive immune responses by influenza A virus. Cell Microbiol 12:873–880 [View Article][PubMed]
    [Google Scholar]
  28. Severa M., Coccia E. M., Fitzgerald K. A. 2006; Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. J Biol Chem 281:26188–26195 [View Article][PubMed]
    [Google Scholar]
  29. Shaveta G., Shi J., Chow V. T., Song J. 2010; Structural characterization reveals that viperin is a radical S-adenosyl-l-methionine (SAM) enzyme. Biochem Biophys Res Commun 391:1390–1395 [View Article][PubMed]
    [Google Scholar]
  30. Stertz S., Shaw M. L. 2011; Uncovering the global host cell requirements for influenza virus replication via RNAi screening. Microbes Infect 13:516–525 [View Article][PubMed]
    [Google Scholar]
  31. Stirnweiss A., Ksienzyk A., Klages K., Rand U., Grashoff M., Hauser H., Kröger A. 2010; IFN regulatory factor-1 bypasses IFN-mediated antiviral effects through viperin gene induction. J Immunol 184:5179–5185 [View Article][PubMed]
    [Google Scholar]
  32. Szretter K. J., Brien J. D., Thackray L. B., Virgin H. W., Cresswell P., Diamond M. S. 2011; The interferon-inducible gene viperin restricts West Nile virus pathogenesis. J Virol 85:11557–11566 [View Article][PubMed]
    [Google Scholar]
  33. Waheed A. A., Freed E. O. 2007; Influenza virus not cRAFTy enough to dodge viperin. Cell Host Microbe 2:71–72 [View Article][PubMed]
    [Google Scholar]
  34. Wang X., Hinson E. R., Cresswell P. 2007; The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe 2:96–105 [View Article][PubMed]
    [Google Scholar]
  35. Watanabe T., Watanabe S., Kawaoka Y. 2010; Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 7:427–439 [View Article][PubMed]
    [Google Scholar]
  36. Whitsett J. A. 2002; Intrinsic and innate defenses in the lung: intersection of pathways regulating lung morphogenesis, host defense, and repair. J Clin Invest 109:565–569[PubMed] [CrossRef]
    [Google Scholar]
  37. Wu S., Metcalf J. P., Wu W. 2011; Innate immune response to influenza virus. Curr Opin Infect Dis 24:235–240 [View Article][PubMed]
    [Google Scholar]
  38. Zhang Y., Burke C. W., Ryman K. D., Klimstra W. B. 2007; Identification and characterization of interferon-induced proteins that inhibit alphavirus replication. J Virol 81:11246–11255 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.040824-0
Loading
/content/journal/jgv/10.1099/vir.0.040824-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
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