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In this study, we begin to examine the effector mechanisms by which type I IFN inhibits WNV infection. Mice lacking both the interferon-induced, double-stranded-RNA-activated protein kinase (PKR) and the endoribonuclease of the 2\u2032,5\u2032-oligoadenylate synthetase-RNase L system (PKR\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \u00d7 RL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) were highly susceptible to subcutaneous WNV infection, with a 90% mortality rate compared to the 30% mortality rate observed in congenic wild-type mice. PKR\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \u00d7 RL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice had increased viral loads in their draining lymph nodes, sera, and spleens, which led to early viral entry into the central nervous system (CNS) and higher viral burden in neuronal tissues. Although mice lacking RNase L showed a higher CNS viral burden and an increased mortality, they were less susceptible than the PKR\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \u00d7 RL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice; thus, we also infer an antiviral role for PKR in the control of WNV infection. Notably, a deficiency in both PKR and RNase L resulted in a decreased ability of type I IFN to inhibit WNV in primary macrophages and cortical neurons. In contrast, the peripheral neurons of the superior cervical ganglia of PKR\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \u00d7 RL\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed no deficiency in the IFN-mediated inhibition of WNV. Our data suggest that PKR and RNase L contribute to IFN-mediated protection in a cell-restricted manner and control WNV infection in peripheral tissues and some neuronal subtypes.\n                  <\/jats:p>","DOI":"10.1128\/jvi.00489-06","type":"journal-article","created":{"date-parts":[[2006,6,28]],"date-time":"2006-06-28T22:27:07Z","timestamp":1151533627000},"page":"7009-7019","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":222,"title":["PKR and RNase L Contribute to Protection against Lethal West Nile Virus Infection by Controlling Early Viral Spread in the Periphery and Replication in Neurons"],"prefix":"10.1128","volume":"80","author":[{"given":"Melanie A.","family":"Samuel","sequence":"first","affiliation":[{"name":"Departments of Molecular Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Whitby","sequence":"additional","affiliation":[{"name":"Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anantha","family":"Marri","sequence":"additional","affiliation":[{"name":"Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"Barchet","sequence":"additional","affiliation":[{"name":"Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, Missouri 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan R. 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