Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury

Lisa E. Gralinski, Armand Bankhead, Sophia Jeng, Vineet 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 & 1 others Ralph S. Baric

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
JournalmBio
Volume4
Issue number4
DOIs
StatePublished - Aug 6 2013
Externally publishedYes

Fingerprint

Severe Acute Respiratory Syndrome
Coronavirus
Acute Lung Injury
Coronavirus Infections
Urokinase-Type Plasminogen Activator
Adult Respiratory Distress Syndrome
Viruses
Knockout Mice
Genes
SARS Virus
H1N1 Subtype Influenza A Virus
Systems Biology
Pulmonary Fibrosis
Gene Regulatory Networks
Fibrinolysin
Orthomyxoviridae
Proteomics
Extracellular Matrix
Pneumonia
Pathology

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Gralinski, L. E., Bankhead, A., Jeng, S., Menachery, V., Proll, S., Belisle, S. E., ... Baric, R. S. (2013). Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio, 4(4). https://doi.org/10.1128/mBio.00271-13

Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. / Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

In: mBio, Vol. 4, No. 4, 06.08.2013.

Research output: Contribution to journalArticle

Gralinski, LE, Bankhead, A, Jeng, S, Menachery, V, Proll, S, Belisle, SE, Matzke, M, Webb-Robertson, BJM, Luna, ML, Shukla, AK, Ferris, MT, Bolles, M, Chang, J, Aicher, L, Waters, KM, Smith, RD, Metz, TO, Law, GL, Katze, MG, McWeeney, S & Baric, RS 2013, 'Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury', mBio, vol. 4, no. 4. https://doi.org/10.1128/mBio.00271-13
Gralinski, Lisa E. ; Bankhead, Armand ; Jeng, Sophia ; Menachery, Vineet ; Proll, Sean ; Belisle, Sarah E. ; Matzke, Melissa ; Webb-Robertson, Bobbie Jo M. ; Luna, Maria L. ; Shukla, Anil K. ; Ferris, Martin T. ; Bolles, Meagan ; Chang, Jean ; Aicher, Lauri ; Waters, Katrina M. ; Smith, Richard D. ; Metz, Thomas O. ; Law, G. Lynn ; Katze, Michael G. ; McWeeney, Shannon ; Baric, Ralph S. / Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. In: mBio. 2013 ; Vol. 4, No. 4.
@article{8ee16108c65e4068b23af5f3e134c154,
title = "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 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.",
author = "Gralinski, {Lisa E.} and Armand Bankhead and Sophia Jeng and Vineet Menachery and Sean Proll and Belisle, {Sarah E.} and Melissa Matzke and Webb-Robertson, {Bobbie Jo M.} and Luna, {Maria L.} and Shukla, {Anil K.} and Ferris, {Martin T.} and Meagan Bolles and Jean Chang and Lauri Aicher and Waters, {Katrina M.} and Smith, {Richard D.} and Metz, {Thomas O.} and Law, {G. Lynn} and Katze, {Michael G.} and Shannon McWeeney and Baric, {Ralph S.}",
year = "2013",
month = "8",
day = "6",
doi = "10.1128/mBio.00271-13",
language = "English (US)",
volume = "4",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury

AU - Gralinski, Lisa E.

AU - Bankhead, Armand

AU - Jeng, Sophia

AU - Menachery, Vineet

AU - Proll, Sean

AU - Belisle, Sarah E.

AU - Matzke, Melissa

AU - Webb-Robertson, Bobbie Jo M.

AU - Luna, Maria L.

AU - Shukla, Anil K.

AU - Ferris, Martin T.

AU - Bolles, Meagan

AU - Chang, Jean

AU - Aicher, Lauri

AU - Waters, Katrina M.

AU - Smith, Richard D.

AU - Metz, Thomas O.

AU - Law, G. Lynn

AU - Katze, Michael G.

AU - McWeeney, Shannon

AU - Baric, Ralph S.

PY - 2013/8/6

Y1 - 2013/8/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84883327100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883327100&partnerID=8YFLogxK

U2 - 10.1128/mBio.00271-13

DO - 10.1128/mBio.00271-13

M3 - Article

VL - 4

JO - mBio

JF - mBio

SN - 2161-2129

IS - 4

ER -