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J. Virol. doi:10.1128/JVI.01151-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

West Nile virus infection activates the unfolded protein response leading to CHOP induction and apoptosis

Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 N.W. 185^th Avenue, Beaverton, OR 97006, Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School ofPublic Health of Columbia University, 722 W 168th Street, 18th Floor, New York, New York 10032, 3.206B Mary Moody Northen Pavilion, Department of Pathology and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0436

^* To whom correspondence should be addressed. Email: medigesh{at}ohsu.edu.

	Abstract

West Nile Virus (WNV)-mediated neuronal death is a hallmark of WNV-meningitis and encephalitis. However, the mechanisms of WNV-induced neuronal damage are not well-understood. We investigated WNV neuropathogenesis using human neuroblastoma cells and primary rat hippocampal neurons. We observed that WNV activates multiple unfolded protein response (UPR) pathways leading to transcriptional and translational induction of UPR target genes. We evaluated the role of the three major UPR pathways in WNV infected cells: inositol-requiring enzyme 1-dependent splicing of X-box-binding protein 1 (XBP1) mRNA, activation of activating transcription factor 6 (ATF6), and PKR-like ER kinase-dependent eIF2 phosphorylation. We show that XBP1 is non-essential or can be substituted by other UPR pathways in WNV replication. ATF6 was rapidly degraded by proteasomes consistent with induction of ER-stress by WNV. We further observed a transient phosphorylation of eukaryotic initiation factor 2 (eIF2) and induction of the pro-apoptotic cAMP response element-binding transcription factor (C/EBP) homologous protein (CHOP). WNV-infected cells exhibited a number of apoptotic phenotypes such as: i) induction of growth arrest and DNA damage inducible gene 34, ii) activation of caspase-3 and iii) cleavage of poly-[ADP-ribose] polymerase. Expression of WNV non-structural proteins alone was sufficient to induce CHOP expression. Importantly, WNV grew to significantly higher viral titers in chop^-/- MEFs compared to wild type MEFs suggesting that CHOP-dependent premature cell death represents a host defense mechanism to limit viral replication that might also be responsible for the wide-spread neuronal loss observed in WNV-infected neuronal tissue.

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