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Journal of Virology, July 2006, p. 7009-7019, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00489-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Melanie A. Samuel,1 Kevin Whitby ,2,{dagger} Brian C. Keller,3 Anantha Marri,2 Winfried Barchet,4 Bryan R. G. Williams,5,{ddagger} Robert H. Silverman,5 Michael Gale Jr.,3 and Michael S. Diamond1,2,4*

Departments of Molecular Microbiology,1 Medicine,2 Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,4 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9048,3 Department of Cancer Biology/NB40, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441955

Received 8 March 2006/ Accepted 17 April 2006

West Nile virus (WNV) is a neurotropic, mosquito-borne flavivirus that can cause lethal meningoencephalitis. Type I interferon (IFN) plays a critical role in controlling WNV replication, spread, and tropism. 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',5'-oligoadenylate synthetase-RNase L system (PKR–/– x RL–/–) 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–/– x RL–/– 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–/– x RL–/– 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–/– x RL–/– 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.

* Corresponding author. Mailing address: Department of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail address: diamond{at}borcim.wustl.edu.

{dagger} Present address: Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, United Kingdom.

{ddagger} Present address: Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia

Journal of Virology, July 2006, p. 7009-7019, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00489-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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