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.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Samuel
authors.forename: Kevin
authors.initials: K
authors.lastname: Whitby
authors.forename: Brian C
authors.initials: BC
authors.lastname: Keller
authors.forename: Anantha
authors.initials: A
authors.lastname: Marri
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D002525:Cerebellar Cortex / Q000201:enzymology / Q000821:virology; D004722:Endoribonucleases / Q000172:deficiency / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000821:virology; D008590:Meningoencephalitis / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology* / Q000821:virology; D009928:Organ Specificity; D017783:Superior Cervical Ganglion / Q000201:enzymology / Q000821:virology; D014779:Virus Replication / Q000235:genetics; D014901:West Nile Fever / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D014902:West Nile virus / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000172:deficiency / Q000378:metabolism*
chemical_list: D007371:Interferon-gamma; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease