Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection

被引:126
作者
Daffis, Stephane [1 ]
Samuel, Melanie A. [2 ]
Suthar, Mehul S. [4 ]
Keller, Brian C. [4 ]
Gale, Michael, Jr. [4 ]
Diamond, Michael S. [1 ,2 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
[4] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA
关键词
D O I
10.1128/JVI.00918-08
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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-a response against WNV occurs through an IRF-7-dependent transcriptional signal.
引用
收藏
页码:8465 / 8475
页数:11
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