Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways a...

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Autores principales:	Lisa E. Gralinski, Armand Bankhead, Sophia Jeng, Vineet D. Menachery, Sean Proll, Sarah E. Belisle, Melissa Matzke, Bobbie-Jo M. Webb-Robertson, Maria L. Luna, Anil K. Shukla, Martin T. Ferris, Meagan Bolles, Jean Chang, Lauri Aicher, Katrina M. Waters, Richard D. Smith, Thomas O. Metz, G. Lynn Law, Michael G. Katze, Shannon McWeeney, Ralph S. Baric
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e5a4def1db8b49f4b6a1891e28591907
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spelling	oai:doaj.org-article:e5a4def1db8b49f4b6a1891e285919072021-11-15T15:43:09ZMechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury10.1128/mBio.00271-132150-7511https://doaj.org/article/e5a4def1db8b49f4b6a1891e285919072013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00271-13https://doaj.org/toc/2150-7511ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. IMPORTANCE Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI.Lisa E. GralinskiArmand BankheadSophia JengVineet D. MenacherySean ProllSarah E. BelisleMelissa MatzkeBobbie-Jo M. Webb-RobertsonMaria L. LunaAnil K. ShuklaMartin T. FerrisMeagan BollesJean ChangLauri AicherKatrina M. WatersRichard D. SmithThomas O. MetzG. Lynn LawMichael G. KatzeShannon McWeeneyRalph S. BaricAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Lisa E. Gralinski Armand Bankhead Sophia Jeng Vineet D. Menachery Sean Proll Sarah E. Belisle Melissa Matzke Bobbie-Jo M. Webb-Robertson Maria L. Luna Anil K. Shukla Martin T. Ferris Meagan Bolles Jean Chang Lauri Aicher Katrina M. Waters Richard D. Smith Thomas O. Metz G. Lynn Law Michael G. Katze Shannon McWeeney Ralph S. Baric Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
description	ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. IMPORTANCE Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI.
format	article
author	Lisa E. Gralinski Armand Bankhead Sophia Jeng Vineet D. Menachery Sean Proll Sarah E. Belisle Melissa Matzke Bobbie-Jo M. Webb-Robertson Maria L. Luna Anil K. Shukla Martin T. Ferris Meagan Bolles Jean Chang Lauri Aicher Katrina M. Waters Richard D. Smith Thomas O. Metz G. Lynn Law Michael G. Katze Shannon McWeeney Ralph S. Baric
author_facet	Lisa E. Gralinski Armand Bankhead Sophia Jeng Vineet D. Menachery Sean Proll Sarah E. Belisle Melissa Matzke Bobbie-Jo M. Webb-Robertson Maria L. Luna Anil K. Shukla Martin T. Ferris Meagan Bolles Jean Chang Lauri Aicher Katrina M. Waters Richard D. Smith Thomas O. Metz G. Lynn Law Michael G. Katze Shannon McWeeney Ralph S. Baric
author_sort	Lisa E. Gralinski
title	Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_short	Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_full	Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_fullStr	Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_full_unstemmed	Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury
title_sort	mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/e5a4def1db8b49f4b6a1891e28591907
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Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

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