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Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury.
mBio. 2013 Aug 06; 4(4)MBIO

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.

Authors+Show Affiliations

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

23919993

Citation

Gralinski, Lisa E., et al. "Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-induced Acute Lung Injury." MBio, vol. 4, no. 4, 2013.
Gralinski LE, Bankhead A, Jeng S, et al. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio. 2013;4(4).
Gralinski, L. E., Bankhead, A., Jeng, S., Menachery, V. D., Proll, S., Belisle, S. E., Matzke, M., Webb-Robertson, B. J., Luna, M. L., Shukla, A. K., Ferris, M. T., Bolles, M., Chang, J., Aicher, L., Waters, K. M., Smith, R. D., Metz, T. O., Law, G. L., Katze, M. G., ... 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
Gralinski LE, et al. Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-induced Acute Lung Injury. mBio. 2013 Aug 6;4(4) PubMed PMID: 23919993.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. AU - Gralinski,Lisa E, AU - Bankhead,Armand,3rd AU - Jeng,Sophia, AU - Menachery,Vineet D, 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, Y1 - 2013/08/06/ PY - 2013/8/8/entrez PY - 2013/8/8/pubmed PY - 2014/1/23/medline JF - mBio JO - mBio VL - 4 IS - 4 N2 - 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. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/23919993/Mechanisms_of_severe_acute_respiratory_syndrome_coronavirus_induced_acute_lung_injury_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=23919993 DB - PRIME DP - Unbound Medicine ER -