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Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection
Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absen...
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| Published in: | PLoS pathogens 2019-10, Vol.15 (10), p.e1008068-e1008068 |
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| creator | Younan, Patrick Santos, Rodrigo I Ramanathan, Palaniappan Iampietro, Mathieu Nishida, Andrew Dutta, Mukta Ammosova, Tatiana Meyer, Michelle Katze, Michael G Popov, Vsevolod L Nekhai, Sergei Bukreyev, Alexander |
| description | Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections. |
| doi_str_mv | 10.1371/journal.ppat.1008068 |
| format | article |
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These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1008068</identifier><identifier>PMID: 31648236</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antigens ; Antigens, Viral - biosynthesis ; Antigens, Viral - genetics ; Apoptosis ; Autophagy ; Autophagy - physiology ; Biology and Life Sciences ; Care and treatment ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - virology ; Cell activation ; Cell death ; Cell fusion ; Cell Line ; Chlorocebus aethiops ; Cytokines ; Dendritic cells ; Depletion ; Ebola hemorrhagic fever ; Ebola virus ; Ebolavirus ; Ebolavirus - immunology ; Endoplasmic Reticulum Stress - physiology ; Epidemics ; Exposure ; Fatalities ; Flow cytometry ; Gene expression ; Genomics ; HEK293 Cells ; Hemorrhagic Fever, Ebola - immunology ; HIV ; Host-Pathogen Interactions ; Human immunodeficiency virus ; Humans ; Indoles - pharmacology ; Infection ; Infections ; Investigations ; Jurkat Cells ; Kinases ; Laboratories ; Lymphocytes ; Lymphocytes T ; Lymphocytopenia ; Lymphopenia ; Lymphopenia - immunology ; Medicine and Health Sciences ; Messenger RNA ; Pathology ; Phagocytosis ; Phosphatases ; Phosphoprotein phosphatase ; Protein phosphatase ; Protein Phosphatase 1 - antagonists & inhibitors ; Research and Analysis Methods ; Risk factors ; RNA Interference ; RNA, Small Interfering - genetics ; RNA, Viral - biosynthesis ; RNA, Viral - genetics ; siRNA ; T cell receptors ; T cells ; Transcription ; Transcription Factors - metabolism ; Urea - analogs & derivatives ; Urea - pharmacology ; Vero Cells ; Viral antigens ; Viral infections ; Viral Proteins - metabolism ; Virus Replication - physiology ; Viruses</subject><ispartof>PLoS pathogens, 2019-10, Vol.15 (10), p.e1008068-e1008068</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Younan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. 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biosynthesis</topic><topic>Antigens, Viral - genetics</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Autophagy - physiology</topic><topic>Biology and Life Sciences</topic><topic>Care and treatment</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - virology</topic><topic>Cell activation</topic><topic>Cell death</topic><topic>Cell fusion</topic><topic>Cell Line</topic><topic>Chlorocebus aethiops</topic><topic>Cytokines</topic><topic>Dendritic cells</topic><topic>Depletion</topic><topic>Ebola hemorrhagic fever</topic><topic>Ebola virus</topic><topic>Ebolavirus</topic><topic>Ebolavirus - immunology</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Epidemics</topic><topic>Exposure</topic><topic>Fatalities</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Genomics</topic><topic>HEK293 Cells</topic><topic>Hemorrhagic Fever, Ebola - immunology</topic><topic>HIV</topic><topic>Host-Pathogen Interactions</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Indoles - 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However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31648236</pmid><doi>10.1371/journal.ppat.1008068</doi><orcidid>https://orcid.org/0000-0001-8121-7647</orcidid><orcidid>https://orcid.org/0000-0003-2548-1288</orcidid><orcidid>https://orcid.org/0000-0002-0342-4824</orcidid><orcidid>https://orcid.org/0000-0003-0744-7887</orcidid><orcidid>https://orcid.org/0000-0001-8777-1032</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2314933793 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Animals Antigens Antigens, Viral - biosynthesis Antigens, Viral - genetics Apoptosis Autophagy Autophagy - physiology Biology and Life Sciences Care and treatment CD4 antigen CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - virology Cell activation Cell death Cell fusion Cell Line Chlorocebus aethiops Cytokines Dendritic cells Depletion Ebola hemorrhagic fever Ebola virus Ebolavirus Ebolavirus - immunology Endoplasmic Reticulum Stress - physiology Epidemics Exposure Fatalities Flow cytometry Gene expression Genomics HEK293 Cells Hemorrhagic Fever, Ebola - immunology HIV Host-Pathogen Interactions Human immunodeficiency virus Humans Indoles - pharmacology Infection Infections Investigations Jurkat Cells Kinases Laboratories Lymphocytes Lymphocytes T Lymphocytopenia Lymphopenia Lymphopenia - immunology Medicine and Health Sciences Messenger RNA Pathology Phagocytosis Phosphatases Phosphoprotein phosphatase Protein phosphatase Protein Phosphatase 1 - antagonists & inhibitors Research and Analysis Methods Risk factors RNA Interference RNA, Small Interfering - genetics RNA, Viral - biosynthesis RNA, Viral - genetics siRNA T cell receptors T cells Transcription Transcription Factors - metabolism Urea - analogs & derivatives Urea - pharmacology Vero Cells Viral antigens Viral infections Viral Proteins - metabolism Virus Replication - physiology Viruses |
| title | Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T09%3A45%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ebola%20virus-mediated%20T-lymphocyte%20depletion%20is%20the%20result%20of%20an%20abortive%20infection&rft.jtitle=PLoS%20pathogens&rft.au=Younan,%20Patrick&rft.date=2019-10-24&rft.volume=15&rft.issue=10&rft.spage=e1008068&rft.epage=e1008068&rft.pages=e1008068-e1008068&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1008068&rft_dat=%3Cgale_plos_%3EA604840194%3C/gale_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c661t-84e44574cb6762411c4c1fb364e4ea221272eb7c583e4c3cff12d5304c3664273%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2314933793&rft_id=info:pmid/31648236&rft_galeid=A604840194&rfr_iscdi=true |