Tumor necrosis factor alpha protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system.
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.
Shrestha
Bimmi
B
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8051, St. Louis, MO 63110, USA.
Zhang
Bo
B
Purtha
Whitney E
WE
Klein
Robyn S
RS
Diamond
Michael S
MS
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001921:Brain / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology* / Q000821:virology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014901:West Nile Fever / Q000276:immunology* / Q000401:mortality / Q000821:virology; D014902:West Nile virus / Q000276:immunology / Q000472:pathogenicity*
D000914:Antibodies, Viral; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha