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Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection.
Title | Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Daffis, S, Samuel, MA, Suthar, MS, Keller, BC, Gale, M, Diamond, MS |
Journal | J Virol |
Volume | 82 |
Issue | 17 |
Pagination | 8465-75 |
Date Published | 2008 Sep |
ISSN | 1098-5514 |
Keywords | Animals, Antiviral Agents, Cells, Cultured, Cerebral Cortex, Crosses, Genetic, Dendritic Cells, Embryo, Mammalian, Fibroblasts, Interferon Regulatory Factor-7, Interferon-alpha, L Cells (Cell Line), Macrophages, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Neurons, RNA, Messenger, RNA, Viral, Survival Analysis, Viral Load, Viremia, West Nile Fever, West Nile virus |
Abstract | 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. |
DOI | 10.1128/JVI.00918-08 |
Alternate Journal | J. Virol. |
PubMed ID | 18562536 |