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Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction...

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Autores principales: Sims, Amy C., Mitchell, Hugh D., Gralinski, Lisa E., Kyle, Jennifer E., Burnum-Johnson, Kristin E., Lam, Mariam, Fulcher, M. Leslie, West, Ande, Smith, Richard D., Randell, Scott H., Metz, Thomas O., Sheahan, Timothy P., Waters, Katrina M., Baric, Ralph S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406233/
https://www.ncbi.nlm.nih.gov/pubmed/34372702
http://dx.doi.org/10.1128/mBio.01572-21
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author Sims, Amy C.
Mitchell, Hugh D.
Gralinski, Lisa E.
Kyle, Jennifer E.
Burnum-Johnson, Kristin E.
Lam, Mariam
Fulcher, M. Leslie
West, Ande
Smith, Richard D.
Randell, Scott H.
Metz, Thomas O.
Sheahan, Timothy P.
Waters, Katrina M.
Baric, Ralph S.
author_facet Sims, Amy C.
Mitchell, Hugh D.
Gralinski, Lisa E.
Kyle, Jennifer E.
Burnum-Johnson, Kristin E.
Lam, Mariam
Fulcher, M. Leslie
West, Ande
Smith, Richard D.
Randell, Scott H.
Metz, Thomas O.
Sheahan, Timothy P.
Waters, Katrina M.
Baric, Ralph S.
author_sort Sims, Amy C.
collection PubMed
description Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction in disease and the identification of critical tissue-specific networks for disease intervention in the lung. Currently, there are no approved therapeutics for Middle East respiratory syndrome coronavirus (MERS-CoV) patients, and little is understood about how lung cell types contribute to disease outcomes. MERS-CoV replicates equivalently in primary human lung microvascular endothelial cells (MVE) and fibroblasts (FB) and to equivalent peak titers but with slower replication kinetics in human airway epithelial cell cultures (HAE). However, only infected MVE demonstrate observable virus-induced cytopathic effect. To explore mechanisms leading to reduced MVE viability, donor-matched human lung MVE, HAE, and FB were infected, and their transcriptomes, proteomes, and lipidomes were monitored over time. Validated functional enrichment analysis demonstrated that MERS-CoV-infected MVE were dying via an unfolded protein response (UPR)-mediated apoptosis. Pharmacologic manipulation of the UPR in MERS-CoV-infected primary lung cells reduced viral titers and in male mice improved respiratory function with accompanying reductions in weight loss, pathological signatures of acute lung injury, and times to recovery. Systems biology analysis and validation studies of global kinetic transcript, protein, and lipid data sets confirmed that inhibition of host stress pathways that are differentially regulated following MERS-CoV infection of different tissue types can alleviate symptom progression to end-stage lung disease commonly seen following emerging coronavirus outbreaks.
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spelling pubmed-84062332021-09-09 Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury Sims, Amy C. Mitchell, Hugh D. Gralinski, Lisa E. Kyle, Jennifer E. Burnum-Johnson, Kristin E. Lam, Mariam Fulcher, M. Leslie West, Ande Smith, Richard D. Randell, Scott H. Metz, Thomas O. Sheahan, Timothy P. Waters, Katrina M. Baric, Ralph S. mBio Research Article Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction in disease and the identification of critical tissue-specific networks for disease intervention in the lung. Currently, there are no approved therapeutics for Middle East respiratory syndrome coronavirus (MERS-CoV) patients, and little is understood about how lung cell types contribute to disease outcomes. MERS-CoV replicates equivalently in primary human lung microvascular endothelial cells (MVE) and fibroblasts (FB) and to equivalent peak titers but with slower replication kinetics in human airway epithelial cell cultures (HAE). However, only infected MVE demonstrate observable virus-induced cytopathic effect. To explore mechanisms leading to reduced MVE viability, donor-matched human lung MVE, HAE, and FB were infected, and their transcriptomes, proteomes, and lipidomes were monitored over time. Validated functional enrichment analysis demonstrated that MERS-CoV-infected MVE were dying via an unfolded protein response (UPR)-mediated apoptosis. Pharmacologic manipulation of the UPR in MERS-CoV-infected primary lung cells reduced viral titers and in male mice improved respiratory function with accompanying reductions in weight loss, pathological signatures of acute lung injury, and times to recovery. Systems biology analysis and validation studies of global kinetic transcript, protein, and lipid data sets confirmed that inhibition of host stress pathways that are differentially regulated following MERS-CoV infection of different tissue types can alleviate symptom progression to end-stage lung disease commonly seen following emerging coronavirus outbreaks. American Society for Microbiology 2021-08-10 /pmc/articles/PMC8406233/ /pubmed/34372702 http://dx.doi.org/10.1128/mBio.01572-21 Text en Copyright © 2021 Sims et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Sims, Amy C.
Mitchell, Hugh D.
Gralinski, Lisa E.
Kyle, Jennifer E.
Burnum-Johnson, Kristin E.
Lam, Mariam
Fulcher, M. Leslie
West, Ande
Smith, Richard D.
Randell, Scott H.
Metz, Thomas O.
Sheahan, Timothy P.
Waters, Katrina M.
Baric, Ralph S.
Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_full Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_fullStr Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_full_unstemmed Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_short Unfolded Protein Response Inhibition Reduces Middle East Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_sort unfolded protein response inhibition reduces middle east respiratory syndrome coronavirus-induced acute lung injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406233/
https://www.ncbi.nlm.nih.gov/pubmed/34372702
http://dx.doi.org/10.1128/mBio.01572-21
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