Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection.
Type I interferon (IFN-alpha/beta) comprises a family of immunomodulatory cytokines that are critical for controlling viral infections. In cell culture, many RNA viruses trigger IFN responses through the binding of RNA recognition molecules (RIG-I, MDA5, and TLR-3) and induction of interferon regulatory factor IRF-3-dependent gene transcription. Recent studies with West Nile virus (WNV) have shown that type I IFN is essential for restricting infection and that a deficiency of IRF-3 results in enhanced lethality. However, IRF-3 was not required for optimal systemic IFN production in vivo or in vitro in macrophages. To begin to define the transcriptional factors that regulate type I IFN after WNV infection, we evaluated IFN induction and virus control in IRF-7(-/-) mice. Compared to congenic wild-type mice, IRF-7(-/-) mice showed increased lethality after WNV infection and developed early and elevated WNV burdens in both peripheral and central nervous system tissues. As a correlate, a deficiency of IRF-7 blunted the systemic type I IFN response in mice. Consistent with this, IFN-alpha gene expression and protein production were reduced and viral titers were increased in IRF-7(-/-) primary macrophages, fibroblasts, dendritic cells, and cortical neurons. In contrast, in these cells the IFN-beta response remained largely intact. Our data suggest that the early protective IFN-alpha response against WNV occurs through an IRF-7-dependent transcriptional signal.
Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Stephane
S
Daffis
Melanie A
MA
Samuel
Mehul S
MS
Suthar
Brian C
BC
Keller
Michael
M
Gale
Michael S
MS
Diamond
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000821:virology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000821:virology; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007739:L Cells; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000821:virology; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D016019:Survival Analysis; D019562:Viral Load; D014766:Viremia; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014902:West Nile virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*
D000998:Antiviral Agents; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D012333:RNA, Messenger; D012367:RNA, Viral