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

@article{citeulike:3177624, abstract = {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. 10.1128/JVI.01118-08}, author = {Shrestha, Bimmi and Zhang, Bo and Purtha, Whitney E. and Klein, Robyn S. and Diamond, Michael S. }, citeulike-article-id = {3177624}, doi = {http://dx.doi.org/10.1128/JVI.01118-08}, journal = {J. Virol.}, keywords = {flavivirus, pathogenesis}, month = {September}, number = {18}, pages = {8956--8964}, posted-at = {2008-09-01 08:25:18}, priority = {2}, title = {Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System}, url = {http://dx.doi.org/10.1128/JVI.01118-08}, volume = {82}, year = {2008} }

TY - JOUR ID - citeulike:3177624 L3 - citeulike-article-id:3177624 N2 - 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. 10.1128/JVI.01118-08 IS - 18 JF - J. Virol. EP - 8964 TI - Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System VL - 82 SP - 8956 KW - flavivirus KW - pathogenesis AU - Shrestha, Bimmi AU - Zhang, Bo AU - Purtha, Whitney AU - Klein, Robyn AU - Diamond, Michael PY - 2008/09/15/ UR - http://dx.doi.org/10.1128/JVI.01118-08 ER -