{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:59:19Z","timestamp":1793109559063,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009306","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000}}],"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"crossref","award":["HDTRA11810039"],"award-info":[{"award-number":["HDTRA11810039"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"crossref","award":["HDTRA11810039"],"award-info":[{"award-number":["HDTRA11810039"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Biohub"},{"DOI":"10.13039\/100006521","name":"School of Medicine, Stanford University","doi-asserted-by":"publisher","award":["Bio-X Interdisciplinary Initiative Program"],"award-info":[{"award-number":["Bio-X Interdisciplinary Initiative Program"]}],"id":[{"id":"10.13039\/100006521","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006521","name":"School of Medicine, Stanford University","doi-asserted-by":"publisher","award":["Maternal and Child Health Research Institute"],"award-info":[{"award-number":["Maternal and Child Health Research Institute"]}],"id":[{"id":"10.13039\/100006521","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Washington School of Medicine","award":["Guy Tribble and Susan Barnes Graduate Discovery Fellowship"],"award-info":[{"award-number":["Guy Tribble and Susan Barnes Graduate Discovery Fellowship"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Venezuelan Equine Encephalitis Virus (VEEV) is a major biothreat agent that naturally causes outbreaks in humans and horses particularly in tropical areas of the western hemisphere, for which no antiviral therapy is currently available. The host response to VEEV and the cellular factors this alphavirus hijacks to support its effective replication or evade cellular immune responses are largely uncharacterized. We have previously demonstrated tremendous cell-to-cell heterogeneity in viral RNA (vRNA) and cellular transcript levels during flaviviral infection using a novel virus-inclusive single-cell RNA-Seq approach. Here, we used this unbiased, genome-wide approach to simultaneously profile the host transcriptome and vRNA in thousands of single cells during infection of human astrocytes with the live-attenuated vaccine strain of VEEV (TC-83). Host transcription was profoundly suppressed, yet \u201csuperproducer cells\u201d with extremely high vRNA abundance emerged during the first viral life cycle and demonstrated an altered transcriptome relative to both uninfected cells and cells with high vRNA abundance harvested at later time points. Additionally, cells with increased structural-to-nonstructural transcript ratio exhibited upregulation of intracellular membrane trafficking genes at later time points. Loss- and gain-of-function experiments confirmed pro- and antiviral activities in both vaccine and virulent VEEV infections among the products of transcripts that positively or negatively correlated with vRNA abundance, respectively. Lastly, comparison with single cell transcriptomic data from other viruses highlighted common and unique pathways perturbed by infection across evolutionary scales. This study provides a high-resolution characterization of the VEEV (TC-83)-host interplay, identifies candidate targets for antivirals, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009306","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T13:45:56Z","timestamp":1617198356000},"page":"e0009306","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["The transcriptional landscape of Venezuelan equine encephalitis virus (TC-83) infection"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5759-9822","authenticated-orcid":true,"given":"Zhiyuan","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-8539","authenticated-orcid":true,"given":"Fabio","family":"Zanini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathish","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwah","family":"Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirle","family":"Saul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishank","family":"Bhalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2733-4110","authenticated-orcid":true,"given":"Nuttada","family":"Panpradist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9782-8829","authenticated-orcid":true,"given":"Avery","family":"Muniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarthi","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-0809","authenticated-orcid":true,"given":"Stephen R.","family":"Quake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6441-4171","authenticated-orcid":true,"given":"Shirit","family":"Einav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"pntd.0009306.ref001","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3390\/v11020164","article-title":"Current Understanding of the Molecular Basis of Venezuelan Equine Encephalitis Virus Pathogenesis and Vaccine Development","author":"A Sharma","year":"2019","journal-title":"Viruses"},{"key":"pntd.0009306.ref002","doi-asserted-by":"crossref","first-page":"721","DOI":"10.2217\/fvl.11.50","article-title":"Endemic Venezuelan equine encephalitis in the Americas: hidden under the dengue umbrella.","volume":"6","author":"PV Aguilar","year":"2011","journal-title":"Future Virol"},{"key":"pntd.0009306.ref003","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev.micro.55.1.235","article-title":"Biological Weapons\u2014a Primer for Microbiologists","author":"RJ Hawley","year":"2001","journal-title":"Annual Review of Microbiology"},{"key":"pntd.0009306.ref004","first-page":"209","article-title":"Others. 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