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Journal of Virology, September 2008, p. 8465-8475, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00918-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interferon Regulatory Factor IRF-7 Induces the Antiviral Alpha Interferon Response and Protects against Lethal West Nile Virus Infection

Stephane Daffis,¹ Melanie A. Samuel,² Mehul S. Suthar,⁴ Brian C. Keller,⁴ Michael Gale Jr.,⁴ and Michael S. Diamond^1,2,3*

Departments of Medicine,¹ Molecular Microbiology,² Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,³ Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650⁴

Received 2 May 2008/ Accepted 4 June 2008

Type I interferon (IFN-/β) 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- 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-β response remained largely intact. Our data suggest that the early protective IFN- response against WNV occurs through an IRF-7-dependent transcriptional signal.

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* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology and Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu

Published ahead of print on 18 June 2008.

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Journal of Virology, September 2008, p. 8465-8475, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00918-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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