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Journal of Virology, September 2008, p. 8956-8964, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01118-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System {triangledown}

Bimmi Shrestha,1 Bo Zhang,1 Whitney E. Purtha,2 Robyn S. Klein,1,2,3 and Michael S. Diamond1,2,4*

Department of Medicine,1 Department of Pathology and Immunology,2 Department of Anatomy and Neurobiology,3 Department of Molecular Microbiology, 660 S. Euclid Ave., Box 8051, Washington University School of Medicine, St. Louis, Missouri 631104

Received 28 May 2008/ Accepted 8 July 2008

West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans, especially in immunocompromised individuals. Previous studies have shown essential protective roles for antiviral cytokines (e.g., alpha interferon [IFN-{alpha}] and IFN-{gamma}) against WNV in mice. However, studies using cell culture offer conflicting answers regarding whether tumor necrosis factor alpha (TNF-{alpha}) has an anti-WNV function. To test the biological significance of TNF-{alpha} against WNV in vivo, experiments were performed with TNF receptor-1 (TNF-R1)-deficient and TNF-{alpha}-depleted C57BL/6 mice. TNF-R1–/– mice had enhanced mortality and decreased survival time after WNV infection compared to congenic wild-type mice. Consistent with this, administration of a neutralizing anti-TNF-{alpha} monoclonal antibody also decreased survival after WNV infection. Relatively small differences in viral burdens in peripheral tissues of TNF-R1–/– mice were observed, and this occurrence correlated with a modest antiviral effect of TNF-{alpha} on primary macrophages but not dendritic cells. In contrast, the viral titers detected in the central nervous systems of TNF-R1–/– mice were significantly increased compared to those of wild-type mice, although TNF-{alpha} did not have a direct antiviral effect in primary neuron cultures. Whereas no defect in priming of adaptive B- and T-cell responses in TNF-R1–/– mice was observed, there were significant reductions in accumulations of CD8+ T cells and macrophages in the brain. Our data are most consistent with a model in which interaction of TNF-{alpha} with TNF-R1 protects against WNV infection by regulating migration of protective inflammatory cells into the brain during acute infection.

* Corresponding author. Mailing address: Department of Medicine, 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

{triangledown} Published ahead of print on 16 July 2008.

Journal of Virology, September 2008, p. 8956-8964, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01118-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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