{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:07:35Z","timestamp":1783462055284,"version":"3.55.0"},"reference-count":63,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["Division of Intramural Research, NIAID\/NIH"],"award-info":[{"award-number":["Division of Intramural Research, NIAID\/NIH"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The unfolded protein response (UPR) maintains protein-folding homeostasis in the endoplasmic reticulum (ER) and has been implicated as both beneficial and detrimental to flavivirus infection. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a sensor of the UPR, is commonly associated with antiviral effects during mosquito-borne flavivirus (MBFV) infection, but its relation to tick-borne flavivirus (TBFV) infection remains largely unexplored. In this study, we identified changes in UPR and autophagic activity during Langat virus (LGTV) infection. LGTV robustly activated UPR and altered autophagic flux. Knockdown of endogenous PERK in human cells resulted in increased LGTV replication, but not that of closely related Powassan virus (POWV). Finally, on examining changes in protein levels of components associated with UPR and autophagy in the absence of PERK, we could show that LGTV-infected cells induced UPR but did not lead to expression of C\/EBP homologous protein (CHOP), an important downstream transcription factor of multiple stress pathways. From these data, we hypothesize that LGTV can antagonize other kinases that target eukaryotic initiation factor 2\u03b1 (eIF2\u03b1), but not PERK, implicating PERK as a potential mediator of intrinsic immunity. This effect was not apparent for POWV, a more pathogenic TBFV, suggesting it may be better equipped to mitigate the antiviral effects of PERK.<\/jats:p>","DOI":"10.3390\/v12030328","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T03:54:14Z","timestamp":1584590054000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["PERK-Mediated Unfolded Protein Response Signaling Restricts Replication of the Tick-Borne Flavivirus Langat Virus"],"prefix":"10.3390","volume":"12","author":[{"given":"Tyler G.","family":"Lewy","sequence":"first","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-1664","authenticated-orcid":false,"given":"Danielle K.","family":"Offerdahl","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0344-2659","authenticated-orcid":false,"given":"Eliza","family":"Kellman","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luwanika","family":"Mlera","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhilash","family":"Chiramel","sequence":"additional","affiliation":[{"name":"Innate Immunity and Pathogenesis Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall E.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Biology of Vector-Borne Viruses Section, Laboratory of Virology, Rocky Mountain Laboratories, NIAID\/NIH, 903 S. 4th St, Hamilton, MT 59840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.chom.2009.04.001","article-title":"Pathogenesis of flavivirus infections: using and abusing the host cell","volume":"5","author":"Mazzon","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"754","DOI":"10.4269\/ajtmh.2012.12-0294","article-title":"Prevalence and genetic characterization of Powassan virus strains infecting Ixodes scapularis in Connecticut","volume":"87","author":"Anderson","year":"2012","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/1756-3305-6-185","article-title":"Isolation of deer tick virus (Powassan virus, lineage II) from Ixodes scapularis and detection of antibody in vertebrate hosts sampled in the Hudson Valley, New York State","volume":"6","author":"Dupuis","year":"2013","journal-title":"Parasit Vectors"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-ento-112408-085446","article-title":"Update on Powassan virus: emergence of a North American tick-borne flavivirus","volume":"55","author":"Ebel","year":"2010","journal-title":"Annu. Rev. Entomol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Paules, C.I., Marston, H.D., Bloom, M.E., and Fauci, A.S. (2018). Tickborne Diseases\u2014Confronting a Growing Threat. N. Engl. J. Med.","DOI":"10.1056\/NEJMp1807870"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"430","DOI":"10.12998\/wjcc.v3.i5.430","article-title":"Tick-borne encephalitis: A review of epidemiology, clinical characteristics, and management","volume":"3","author":"Bogovic","year":"2015","journal-title":"World J. Clin. Cases"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1186\/1756-3305-7-443","article-title":"Prevalence and phylogenetic analysis of tick-borne encephalitis virus (TBEV) in field-collected ticks (Ixodes ricinus) in southern Switzerland","volume":"7","author":"Rieille","year":"2014","journal-title":"Parasit Vectors"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1289\/ehp.1307799","article-title":"Estimated effects of projected climate change on the basic reproductive number of the Lyme disease vector Ixodes scapularis","volume":"122","author":"Ogden","year":"2014","journal-title":"Environ. Health Perspect"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1093\/cid\/civ1005","article-title":"Emerging Cases of Powassan Virus Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature","volume":"62","author":"Piantadosi","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1097\/NEN.0000000000000131","article-title":"A tick-borne encephalitis model in infant rats infected with langat virus","volume":"73","author":"Maffioli","year":"2014","journal-title":"J. Neuropathol Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0092-8674(00)81360-4","article-title":"A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response","volume":"87","author":"Cox","year":"1996","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/0092-8674(89)90058-5","article-title":"KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP\/GRP78 gene","volume":"57","author":"Rose","year":"1989","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/sj.emboj.7601477","article-title":"Unfolded protein response in a Drosophila model for retinal degeneration","volume":"26","author":"Ryoo","year":"2007","journal-title":"EMBO J."},{"key":"ref_14","first-page":"291","article-title":"BiP: Master Regulator of the Unfolded Protein Response and Crucial Factor in Flavivirus Biology","volume":"90","author":"Lewy","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated translation initiation controls stress-induced gene expression in mammalian cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37375","DOI":"10.1074\/jbc.M303619200","article-title":"Induction of Grp78\/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF\/CRE site independent of the endoplasmic reticulum stress elements","volume":"278","author":"Luo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1083\/jcb.108.6.2117","article-title":"Interactions of misfolded influenza virus hemagglutinin with binding protein (BiP)","volume":"108","author":"Hurtley","year":"1989","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12747","DOI":"10.1128\/JVI.78.23.12747-12761.2004","article-title":"Resistance to vesicular stomatitis virus infection requires a functional cross talk between the eukaryotic translation initiation factor 2alpha kinases PERK and PKR","volume":"78","author":"Baltzis","year":"2004","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.tim.2005.02.004","article-title":"Hepatitis C virus, ER stress, and oxidative stress","volume":"13","author":"Tardif","year":"2005","journal-title":"Trends Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9588","DOI":"10.1128\/JVI.76.19.9588-9599.2002","article-title":"Replication of a cytopathic strain of bovine viral diarrhea virus activates PERK and induces endoplasmic reticulum stress-mediated apoptosis of MDBK cells","volume":"76","author":"Jordan","year":"2002","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6890","DOI":"10.1128\/JVI.79.11.6890-6899.2005","article-title":"Human cytomegalovirus infection activates and regulates the unfolded protein response","volume":"79","author":"Isler","year":"2005","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12871","DOI":"10.1128\/JVI.01419-09","article-title":"Dengue virus infection induces upregulation of GRP78, which acts to chaperone viral antigen production","volume":"83","author":"Wati","year":"2009","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/1743-422X-8-128","article-title":"Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity","volume":"8","author":"Wu","year":"2011","journal-title":"Virol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10849","DOI":"10.1128\/JVI.01151-07","article-title":"West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis","volume":"81","author":"Medigeshi","year":"2007","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14226","DOI":"10.1074\/jbc.M111.222703","article-title":"Dengue virus modulates the unfolded protein response in a time-dependent manner","volume":"286","author":"Pena","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1128\/JVI.02050-10","article-title":"West Nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion","volume":"85","author":"Ambrose","year":"2011","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2127","DOI":"10.1038\/cddis.2015.409","article-title":"Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation","volume":"7","author":"Datan","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1038\/s41467-019-11663-2","article-title":"Viral priming of cell intrinsic innate antiviral signaling by the unfolded protein response","volume":"10","author":"Carletti","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.virusres.2013.10.012","article-title":"Tick-borne encephalitis virus triggers inositol-requiring enzyme 1 (IRE1) and transcription factor 6 (ATF6) pathways of unfolded protein response","volume":"178","author":"Yu","year":"2013","journal-title":"Virus Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.mib.2013.03.010","article-title":"The role of \u201ceat-me\u201d signals and autophagy cargo receptors in innate immunity","volume":"16","author":"Boyle","year":"2013","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4161\/auto.7.3.14487","article-title":"Selective autophagy mediated by autophagic adapter proteins","volume":"7","author":"Johansen","year":"2011","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1152\/physrev.00030.2009","article-title":"Regulation of mammalian autophagy in physiology and pathophysiology","volume":"90","author":"Ravikumar","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41579-018-0003-6","article-title":"Autophagy during viral infection - a double-edged sword","volume":"16","author":"Choi","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1084\/jem.20170957","article-title":"Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice","volume":"214","author":"Cao","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/1348-0421.12440","article-title":"Impaired Japanese encephalitis virus replication in p62\/SQSTM1 deficient mouse embryonic fibroblasts","volume":"60","author":"Tasaki","year":"2016","journal-title":"Microbiol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.chom.2010.10.006","article-title":"Dengue virus-induced autophagy regulates lipid metabolism","volume":"8","author":"Heaton","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.virol.2008.02.016","article-title":"Autophagic machinery activated by dengue virus enhances virus replication","volume":"374","author":"Lee","year":"2008","journal-title":"Virology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8026","DOI":"10.1128\/JVI.00787-15","article-title":"Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62","volume":"89","author":"Metz","year":"2015","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.virol.2012.08.016","article-title":"West Nile virus growth is independent of autophagy activation","volume":"433","author":"Beatman","year":"2012","journal-title":"Virology"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Vandergaast, R., and Fredericksen, B.L. (2012). West Nile virus (WNV) replication is independent of autophagy in mammalian cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045800"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mlera, L., Meade-White, K., Saturday, G., Scott, D., and Bloom, M.E. (2017). Modeling Powassan virus infection in Peromyscus leucopus, a natural host. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005346"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Offerdahl, D.K., Dorward, D.W., Hansen, B.T., and Bloom, M.E. (2012). A three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047912"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Grabowski, J.M., Perera, R., Roumani, A.M., Hedrick, V.E., Inerowicz, H.D., Hill, C.A., and Kuhn, R.J. (2016). Changes in the Proteome of Langat-Infected Ixodes scapularis ISE6 Cells: Metabolic Pathways Associated with Flavivirus Infection. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004180"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Grabowski, J.M., Tsetsarkin, K.A., Long, D., Scott, D.P., Rosenke, R., Schwan, T.G., Mlera, L., Offerdahl, D.K., Pletnev, A.G., and Bloom, M.E. (2017). Flavivirus Infection of Ixodes scapularis (Black-Legged Tick) Ex Vivo Organotypic Cultures and Applications for Disease Control. MBio, 8.","DOI":"10.1128\/mBio.01255-17"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e00614","DOI":"10.1128\/mBio.00614-15","article-title":"Development of a Model System for Tick-Borne Flavivirus Persistence in HEK 293T Cells","volume":"6","author":"Mlera","year":"2015","journal-title":"MBio"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/B978-0-12-385114-7.00004-0","article-title":"Measuring ER stress and the unfolded protein response using mammalian tissue culture system","volume":"490","author":"Oslowski","year":"2011","journal-title":"Methods Enzymol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/jb\/mvr143","article-title":"CHOP is a multifunctional transcription factor in the ER stress response","volume":"151","author":"Nishitoh","year":"2012","journal-title":"J. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Yang, Z., Xu, Y., Xu, L., Maccauro, G., Rossi, B., Chen, Y., Li, H., Zhang, J., Sun, H., and Yang, Y. (2013). Regulation of autophagy via PERK-eIF2alpha effectively relieve the radiation myelitis induced by iodine-125. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076819"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/sj.cdd.4401984","article-title":"ER stress (PERK\/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation","volume":"14","author":"Kouroku","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1093\/hmg\/ddm002","article-title":"Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin\/proteasome ERAD(I) and autophagy\/lysosome ERAD(II)","volume":"16","author":"Fujita","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/S1097-2765(01)00264-7","article-title":"Diabetes mellitus and exocrine pancreatic dysfunction in perk-\/- mice reveals a role for translational control in secretory cell survival","volume":"7","author":"Harding","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12828","DOI":"10.1128\/JVI.79.20.12828-12839.2005","article-title":"Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist","volume":"79","author":"Best","year":"2005","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Diamond, M.S. (2009). Virus and host determinants of West Nile virus pathogenesis. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000452"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3389\/fmicb.2014.00266","article-title":"Stress responses in flavivirus-infected cells: Activation of unfolded protein response and autophagy","volume":"5","author":"Blazquez","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.3389\/fimmu.2017.01612","article-title":"Transcription Factor C\/EBP Homologous Protein in Health and Diseases","volume":"8","author":"Yang","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Williams, B.R. (2001). Signal integration via PKR. Sci. STKE, 2001.","DOI":"10.1126\/stke.2001.89.re2"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6909","DOI":"10.1093\/emboj\/20.23.6909","article-title":"Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency","volume":"20","author":"Han","year":"2001","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-3-642-56688-2_6","article-title":"Regulation of translation initiation by amino acids in eukaryotic cells","volume":"26","author":"Kimball","year":"2001","journal-title":"Prog. Mol. Subcell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.virol.2011.08.008","article-title":"West Nile virus infection does not induce PKR activation in rodent cells","volume":"421","author":"Elbahesh","year":"2011","journal-title":"Virology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"10347","DOI":"10.1128\/JVI.00525-12","article-title":"Blocking double-stranded RNA-activated protein kinase PKR by Japanese encephalitis virus nonstructural protein 2A","volume":"86","author":"Tu","year":"2012","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1021\/acsinfecdis.7b00274","article-title":"The Use of Ex Vivo Organ Cultures in Tick-Borne Virus Research","volume":"4","author":"Grabowski","year":"2018","journal-title":"ACS Infect. Dis."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/3\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:07:38Z","timestamp":1760173658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/12\/3\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,18]]},"references-count":63,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["v12030328"],"URL":"https:\/\/doi.org\/10.3390\/v12030328","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,18]]}}}