1887

Abstract

STAT1-deficient mice are more susceptible to infection with severe acute respiratory syndrome coronavirus (SARS-CoV) than type I interferon (IFN) receptor-deficient mice. We used mice lacking functional receptors for both type I and type III IFN (double knockout, dKO) to evaluate the possibility that type III IFN plays a decisive role in SARS-CoV protection. We found that viral peak titres in lungs of dKO and STAT1-deficient mice were similar, but significantly higher than in wild-type mice. The kinetics of viral clearance from the lung were also comparable in dKO and STAT1-deficient mice. Surprisingly, however, infected dKO mice remained healthy, whereas infected STAT1-deficient mice developed liver pathology and eventually succumbed to neurological disease. Our data suggest that the failure of STAT1-deficient mice to control initial SARS-CoV replication efficiently in the lung is due to impaired type I and type III IFN signalling, whereas the failure to control subsequent systemic viral spread is due to unrelated defects in STAT1-deficient mice.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.046284-0
2012-12-01
2024-11-04
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/12/2601.html?itemId=/content/journal/jgv/10.1099/vir.0.046284-0&mimeType=html&fmt=ahah

References

  1. Aaronson D. S., Horvath C. M. 2002; A road map for those who don’t know JAK-STAT. Science 296:1653–1655 [View Article][PubMed]
    [Google Scholar]
  2. Ank N., West H., Paludan S. R. 2006; IFN-λ: novel antiviral cytokines. J Interferon Cytokine Res 26:373–379 [View Article][PubMed]
    [Google Scholar]
  3. Cinatl J., Morgenstern B., Bauer G., Chandra P., Rabenau H., Doerr H. W. 2003; Treatment of SARS with human interferons. Lancet 362:293–294 [View Article][PubMed]
    [Google Scholar]
  4. Ding Y., Wang H., Shen H., Li Z., Geng J., Han H., Cai J., Li X., Kang W. other authors 2003; The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol 200:282–289 [View Article][PubMed]
    [Google Scholar]
  5. Drosten C., Günther S., Preiser W., van der Werf S., Brodt H. R., Becker S., Rabenau H., Panning M., Kolesnikova L. other authors 2003; Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348:1967–1976 [View Article][PubMed]
    [Google Scholar]
  6. Farcas G. A., Poutanen S. M., Mazzulli T., Willey B. M., Butany J., Asa S. L., Faure P., Akhavan P., Low D. E., Kain K. C. 2005; Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus. J Infect Dis 191:193–197 [View Article][PubMed]
    [Google Scholar]
  7. Frieman M. B., Chen J., Morrison T. E., Whitmore A., Funkhouser W., Ward J. M., Lamirande E. W., Roberts A., Heise M. other authors 2010; SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6:e1000849 [View Article][PubMed]
    [Google Scholar]
  8. Glass W. G., Subbarao K., Murphy B., Murphy P. M. 2004; Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173:4030–4039[PubMed] [CrossRef]
    [Google Scholar]
  9. Glass W. G., Lim J. K., Cholera R., Pletnev A. G., Gao J. L., Murphy P. M. 2005; Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J Exp Med 202:1087–1098 [View Article][PubMed]
    [Google Scholar]
  10. Haagmans B. L., Kuiken T., Martina B. E., Fouchier R. A., Rimmelzwaan G. F., van Amerongen G., van Riel D., de Jong T., Itamura S. other authors 2004; Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 10:290–293 [View Article][PubMed]
    [Google Scholar]
  11. Haller O., Kochs G., Weber F. 2006; The interferon response circuit: induction and suppression by pathogenic viruses. Virology 344:119–130 [View Article][PubMed]
    [Google Scholar]
  12. Hensley L. E., Fritz L. E., Jahrling P. B., Karp C. L., Huggins J. W., Geisbert T. W. 2004; Interferon-β 1a and SARS coronavirus replication. Emerg Infect Dis 10:317–319 [View Article][PubMed]
    [Google Scholar]
  13. Hickey M. J., Held K. S., Baum E., Gao J. L., Murphy P. M., Lane T. E. 2007; CCR1 deficiency increases susceptibility to fatal coronavirus infection of the central nervous system. Viral Immunol 20:599–608 [View Article][PubMed]
    [Google Scholar]
  14. Hogan R. J., Gao G., Rowe T., Bell P., Flieder D., Paragas J., Kobinger G. P., Wivel N. A., Crystal R. G. other authors 2004; Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1. J Virol 78:11416–11421 [View Article][PubMed]
    [Google Scholar]
  15. Kotenko S. V., Gallagher G., Baurin V. V., Lewis-Antes A., Shen M., Shah N. K., Langer J. A., Sheikh F., Dickensheets H., Donnelly R. P. 2003; IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4:69–77 [View Article][PubMed]
    [Google Scholar]
  16. Le Bon A., Tough D. F. 2002; Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14:432–436 [View Article][PubMed]
    [Google Scholar]
  17. Leung W. K., To K. F., Chan P. K., Chan H. L., Wu A. K., Lee N., Yuen K. Y., Sung J. J. 2003; Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology 125:1011–1017 [View Article][PubMed]
    [Google Scholar]
  18. Mellado M., Rodríguez-Frade J. M., Mañes S., Martínez-A C. 2001; Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Annu Rev Immunol 19:397–421 [View Article][PubMed]
    [Google Scholar]
  19. Mordstein M., Kochs G., Dumoutier L., Renauld J. C., Paludan S. R., Klucher K., Staeheli P. 2008; Interferon-λ contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog 4:e1000151 [View Article][PubMed]
    [Google Scholar]
  20. Mordstein M., Neugebauer E., Ditt V., Jessen B., Rieger T., Falcone V., Sorgeloos F., Ehl S., Mayer D. other authors 2010; Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol 84:5670–5677 [View Article][PubMed]
    [Google Scholar]
  21. Morrow M. P., Pankhong P., Laddy D. J., Schoenly K. A., Yan J., Cisper N., Weiner D. B. 2009; Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood 113:5868–5877 [View Article][PubMed]
    [Google Scholar]
  22. Peiris J. S., Chu C. M., Cheng V. C., Chan K. S., Hung I. F., Poon L. L., Law K. I., Tang B. S., Hon T. Y. other authors 2003a; Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361:1767–1772 [View Article][PubMed]
    [Google Scholar]
  23. Peiris J. S., Lai S. T., Poon L. L., Guan Y., Yam L. Y., Lim W., Nicholls J., Yee W. K., Yan W. W. other authors 2003b; Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361:1319–1325 [View Article][PubMed]
    [Google Scholar]
  24. Pott J., Mahlakõiv T., Mordstein M., Duerr C. U., Michiels T., Stockinger S., Staeheli P., Hornef M. W. 2011; IFN-λ determines the intestinal epithelial antiviral host defense. Proc Natl Acad Sci U S A 108:7944–7949 [View Article][PubMed]
    [Google Scholar]
  25. Radonić A., Thulke S., Mackay I. M., Landt O., Siegert W., Nitsche A. 2004; Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun 313:856–862 [View Article][PubMed]
    [Google Scholar]
  26. Roberts A., Deming D., Paddock C. D., Cheng A., Yount B., Vogel L., Herman B. D., Sheahan T., Heise M. other authors 2007; A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog 3:e5 [View Article][PubMed]
    [Google Scholar]
  27. Sadler A. J., Williams B. R. 2008; Interferon-inducible antiviral effectors. Nat Rev Immunol 8:559–568 [View Article][PubMed]
    [Google Scholar]
  28. Sheahan T., Morrison T. E., Funkhouser W., Uematsu S., Akira S., Baric R. S., Heise M. T. 2008; MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog 4:e1000240 [View Article][PubMed]
    [Google Scholar]
  29. Skowronski D. M., Astell C., Brunham R. C., Low D. E., Petric M., Roper R. L., Talbot P. J., Tam T., Babiuk L. 2005; Severe acute respiratory syndrome (SARS): a year in review. Annu Rev Med 56:357–381 [View Article][PubMed]
    [Google Scholar]
  30. Uzé G., Schreiber G., Piehler J., Pellegrini S. 2007; The receptor of the type I interferon family. Curr Top Microbiol Immunol 316:71–95 [View Article][PubMed]
    [Google Scholar]
  31. Zheng B., He M. L., Wong K. L., Lum C. T., Poon L. L., Peng Y., Guan Y., Lin M. C., Kung H. F. 2004; Potent inhibition of SARS-associated coronavirus (SCOV) infection and replication by type I interferons (IFN-α/β) but not by type II interferon (IFN-γ). J Interferon Cytokine Res 24:388–390 [View Article][PubMed]
    [Google Scholar]
  32. Zhou Z., Hamming O. J., Ank N., Paludan S. R., Nielsen A. L., Hartmann R. 2007; Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol 81:7749–7758 [View Article][PubMed]
    [Google Scholar]
/content/journal/jgv/10.1099/vir.0.046284-0
Loading
/content/journal/jgv/10.1099/vir.0.046284-0
Loading

Data & Media loading...

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