Cell-specific IRF-3 responses protect against West Nile virus infection by interferon-dependent and -independent mechanisms.
Interferon regulatory factor (IRF)-3 is a master transcription factor that activates host antiviral defense programs. Although cell culture studies suggest that IRF-3 promotes antiviral control by inducing interferon (IFN)-beta, near normal levels of IFN-alpha and IFN-beta were observed in IRF-3(-/-) mice after infection by several RNA and DNA viruses. Thus, the specific mechanisms by which IRF-3 modulates viral infection remain controversial. Some of this disparity could reflect direct IRF-3-dependent antiviral responses in specific cell types to control infection. To address this and determine how IRF-3 coordinates an antiviral response, we infected IRF-3(-/-) mice and two primary cells relevant for West Nile virus (WNV) pathogenesis, macrophages and cortical neurons. IRF-3(-/-) mice were uniformly vulnerable to infection and developed elevated WNV burdens in peripheral and central nervous system tissues, though peripheral IFN responses were largely normal. Whereas wild-type macrophages basally expressed key host defense molecules, including RIG-I, MDA5, ISG54, and ISG56, and restricted WNV infection, IRF-3(-/-) macrophages lacked basal expression of these host defense genes and supported increased WNV infection and IFN-alpha and IFN-beta production. In contrast, wild-type cortical neurons were highly permissive to WNV and did not basally express RIG-I, MDA5, ISG54, and ISG56. IRF-3(-/-) neurons lacked induction of host defense genes and had blunted IFN-alpha and IFN-beta production, yet exhibited only modestly increased viral titers. Collectively, our data suggest that cell-specific IRF-3 responses protect against WNV infection through both IFN-dependent and -independent programs.
Department of Medicine, Washington University School of Medicine, St. Louis. Missouri, United States of America.
Stephane
S
Daffis
Melanie A
MA
Samuel
Brian C
BC
Keller
Michael
M
Gale
Michael S
MS
Diamond
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D012333:RNA, Messenger / Q000378:metabolism; D014779:Virus Replication; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology / Q000472:pathogenicity*
D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D012333:RNA, Messenger; D016899:Interferon-beta