{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:19:03Z","timestamp":1790857143901,"version":"4.1.0"},"reference-count":64,"publisher":"American Society for Microbiology","issue":"20","license":[{"start":{"date-parts":[[2007,10,15]],"date-time":"2007-10-15T00:00:00Z","timestamp":1192406400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2007,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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 by 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, namely, inositol-requiring enzyme 1-dependent splicing of X box binding protein 1 (XBP1) mRNA, activation of activating transcription factor 6 (ATF6), and protein kinase R-like endoplasmic reticulum (ER) kinase-dependent eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) phosphorylation, in WNV-infected cells. We show that XBP1 is nonessential or can be replaced 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 eIF2\u03b1 and induction of the proapoptotic cyclic AMP response element-binding transcription factor 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. The expression of WNV nonstructural proteins alone was sufficient to induce CHOP expression. Importantly, WNV grew to significantly higher viral titers in\n            <jats:italic>chop<\/jats:italic>\n            <jats:sup>\u2212<\/jats:sup>\n            <jats:sup>\/<\/jats:sup>\n            <jats:sup>\u2212<\/jats:sup>\n            mouse embryonic fibroblasts (MEFs) than in 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 widespread neuronal loss observed in WNV-infected neuronal tissue.\n          <\/jats:p>","DOI":"10.1128\/jvi.01151-07","type":"journal-article","created":{"date-parts":[[2007,8,9]],"date-time":"2007-08-09T00:48:34Z","timestamp":1186620514000},"page":"10849-10860","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":220,"title":["West Nile Virus Infection Activates the Unfolded Protein Response, Leading to CHOP Induction and Apoptosis"],"prefix":"10.1128","volume":"81","author":[{"given":"Guruprasad R.","family":"Medigeshi","sequence":"first","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa M.","family":"Lancaster","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec J.","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Briese","sequence":"additional","affiliation":[{"name":"Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health of Columbia University, 722 West 168th Street, 18th Floor, New York, New York 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Ian","family":"Lipkin","sequence":"additional","affiliation":[{"name":"Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health of Columbia University, 722 West 168th Street, 18th Floor, New York, New York 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"DeFilippis","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Fru\u0308h","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Mason","sequence":"additional","affiliation":[{"name":"3.206B Mary Moody Northen Pavilion, Department of Pathology and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0436"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janko","family":"Nikolich-Zugich","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay A.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute, Oregon Health &amp; Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10731"},{"key":"e_1_3_2_3_2","unstructured":"Applied Biosystems 1997"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02220-0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/415092a"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-3455fje"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110636200"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20959"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00116-1"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.10.12.8903508"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.23.12617-12629.2003"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.02.036"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2004.04.008"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.18.011402.160624"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/16729"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.3.843"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.18.11943-11951.2005"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20118"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.19.9588-9599.2002"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.356"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.8.3415-3429.2004"},{"key":"e_1_3_2_22_2","first-page":"1573","volume":"17","year":"2003","unstructured":"Kojima, E., A. 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