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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.
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页码:8465 / 8475
页数:11
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