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
2019-10-18
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. [CrossRef] [PubMed]
    [Google Scholar]
  2. Ank N. , West H. , Paludan S. R. . ( 2006; ). IFN-λ: novel antiviral cytokines. . J Interferon Cytokine Res 26:, 373–379. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
  27. Sadler A. J. , Williams B. R. . ( 2008; ). Interferon-inducible antiviral effectors. . Nat Rev Immunol 8:, 559–568. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.046284-0
Loading
/content/journal/jgv/10.1099/vir.0.046284-0
Loading

Data & Media loading...

Most Cited This Month

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