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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2021
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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. |
format | Online Article Text |
id | pubmed-8406233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
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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