Cell-Specific IRF-3 Responses Protect against West Nile Virus Infection by Interferon-Dependent and -Independent Mechanisms

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Abstract
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)-β, near normal levels of IFN-α and IFN-β 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-α and IFN-β 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-α and IFN-β 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. West Nile virus (WNV) is a mosquito-transmitted RNA virus that infects birds, horses, and humans, and it has become an emerging infectious disease threat in the Western hemisphere, including all of the continental United States. WNV invades the brain and spinal cord and infects and injures neurons, causing severe neurological disease, including encephalitis and paralysis, primarily in the immunocompromised and elderly. An increased understanding of how the immune system recognizes WNV and promotes an antiviral defense is vital to developing novel therapeutics and vaccines that limit disease, and identifying individuals at high risk for severe disease. In this study, using a mouse model of WNV pathogenesis, we evaluate the functional role of interferon regulatory factor 3 (IRF-3), a master transcriptional regulator of interferon induction and antiviral responses, in controlling infection. Mice that lack IRF-3 were uniformly susceptible to severe infection with 100% lethality. We observed cell-type–specific responses, as neurons and macrophages utilized IRF-3 to protect against WNV infection through distinct antiviral pathways. Finally, IRF-3 also appears to regulate the basal expression of specific sensors of viral infection, which in turn affects the antiviral state of a cell prior to virus entry.