U.S. Department of Energy

Pacific Northwest National Laboratory

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

TitleMechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury.
Publication TypeJournal Article
Year of Publication2013
AuthorsGralinski LE, Bankhead A, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson B-JM, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, G Law L, Katze MG, McWeeney S, Baric RS
JournalMBio
KeywordsAcute Lung Injury, Animals, Blood Coagulation, Disease Models, Animal, Fibrinolysis, Gene Expression Profiling, Host-Pathogen Interactions, Lung, Mice, Mice, Inbred C57BL, Mice, Knockout, Proteome, SARS Virus, Time Factors, Urokinase-Type Plasminogen Activator
Abstract

UNLABELLED: 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.

DOI10.1128/mBio.00271-13
Alternate JournalMBio
PubMed ID23919993
PubMed Central IDPMC3747576
Grant List5UL1RR024140 / RR / NCRR NIH HHS / United States
8 P41 GM103493-10 / GM / NIGMS NIH HHS / United States
HHSN272200800060C / / PHS HHS / United States
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