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Previous studies have shown essential protective roles for antiviral cytokines (e.g., alpha interferon [IFN-\u03b1] and IFN-\u03b3) against WNV in mice. However, studies using cell culture offer conflicting answers regarding whether tumor necrosis factor alpha (TNF-\u03b1) has an anti-WNV function. To test the biological significance of TNF-\u03b1 against WNV in vivo, experiments were performed with TNF receptor-1 (TNF-R1)-deficient and TNF-\u03b1-depleted C57BL\/6 mice. TNF-R1<jats:sup>\u2212\/\u2212<\/jats:sup>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-\u03b1 monoclonal antibody also decreased survival after WNV infection. Relatively small differences in viral burdens in peripheral tissues of TNF-R1<jats:sup>\u2212\/\u2212<\/jats:sup>mice were observed, and this occurrence correlated with a modest antiviral effect of TNF-\u03b1 on primary macrophages but not dendritic cells. In contrast, the viral titers detected in the central nervous systems of TNF-R1<jats:sup>\u2212\/\u2212<\/jats:sup>mice were significantly increased compared to those of wild-type mice, although TNF-\u03b1 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<jats:sup>\u2212\/\u2212<\/jats:sup>mice was observed, there were significant reductions in accumulations of CD8<jats:sup>+<\/jats:sup>T cells and macrophages in the brain. Our data are most consistent with a model in which interaction of TNF-\u03b1 with TNF-R1 protects against WNV infection by regulating migration of protective inflammatory cells into the brain during acute infection.<\/jats:p>","DOI":"10.1128\/jvi.01118-08","type":"journal-article","created":{"date-parts":[[2008,7,17]],"date-time":"2008-07-17T01:06:03Z","timestamp":1216256763000},"page":"8956-8964","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":92,"title":["Tumor Necrosis Factor Alpha Protects against Lethal West Nile Virus Infection by Promoting Trafficking of Mononuclear Leukocytes into the Central Nervous System"],"prefix":"10.1128","volume":"82","author":[{"given":"Bimmi","family":"Shrestha","sequence":"first","affiliation":[{"name":"Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney E.","family":"Purtha","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn S.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Medicine"},{"name":"Department of Pathology and Immunology"},{"name":"Department of Anatomy and Neurobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Medicine"},{"name":"Department of Pathology and Immunology"},{"name":"Department of Molecular Microbiology, 660 S. 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