In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 15, No. 3 ( 2021-3-31), p. e0009306-
Abstract:
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 “superproducer cells” 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.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0009306
DOI:
10.1371/journal.pntd.0009306.g001
DOI:
10.1371/journal.pntd.0009306.g002
DOI:
10.1371/journal.pntd.0009306.g003
DOI:
10.1371/journal.pntd.0009306.g004
DOI:
10.1371/journal.pntd.0009306.g005
DOI:
10.1371/journal.pntd.0009306.g006
DOI:
10.1371/journal.pntd.0009306.s001
DOI:
10.1371/journal.pntd.0009306.s002
DOI:
10.1371/journal.pntd.0009306.s003
DOI:
10.1371/journal.pntd.0009306.s004
DOI:
10.1371/journal.pntd.0009306.s005
DOI:
10.1371/journal.pntd.0009306.s006
DOI:
10.1371/journal.pntd.0009306.s007
DOI:
10.1371/journal.pntd.0009306.s008
DOI:
10.1371/journal.pntd.0009306.s009
DOI:
10.1371/journal.pntd.0009306.s010
DOI:
10.1371/journal.pntd.0009306.s011
DOI:
10.1371/journal.pntd.0009306.r001
DOI:
10.1371/journal.pntd.0009306.r002
DOI:
10.1371/journal.pntd.0009306.r003
DOI:
10.1371/journal.pntd.0009306.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2429704-5
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