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.
  
  
  OBJECTIVE
  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.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Gralinski
authors.forename: Armand
authors.initials: A
authors.lastname: Bankhead
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.forename: Vineet D
authors.initials: VD
authors.lastname: Menachery
authors.forename: Sean
authors.initials: S
authors.lastname: Proll
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Belisle
authors.forename: Melissa
authors.initials: M
authors.lastname: Matzke
authors.forename: Bobbie-Jo M
authors.initials: BJ
authors.lastname: Webb-Robertson
authors.forename: Maria L
authors.initials: ML
authors.lastname: Luna
authors.forename: Anil K
authors.initials: AK
authors.lastname: Shukla
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.forename: Meagan
authors.initials: M
authors.lastname: Bolles
authors.forename: Jean
authors.initials: J
authors.lastname: Chang
authors.forename: Lauri
authors.initials: L
authors.lastname: Aicher
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
authors.forename: G Lynn
authors.initials: GL
authors.lastname: Law
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology* / Q000821:virology*; D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D005342:Fibrinolysis; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D008168:Lung / Q000473:pathology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020543:Proteome / Q000032:analysis; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity*; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D020543:Proteome; D014568:Urokinase-Type Plasminogen Activator
references.citation: Mod Pathol. 2005 Jan;18(1):1-10
references.pmid: 15272286
references.citation: Nat Commun. 2012 Apr 10;3:771
references.pmid: 22491319
references.citation: Thromb Res. 2012 Oct;130(4):576-85
references.pmid: 22801256
references.citation: BMC Bioinformatics. 2010 Apr 06;11:170
references.pmid: 20370926
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
references.pmid: 17090670
references.citation: Jpn J Infect Dis. 2008 Mar;61(2):157-60
references.pmid: 18362412
references.citation: Hum Pathol. 2003 Aug;34(8):743-8
references.pmid: 14506633
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Aug;301(2):L247-54
references.pmid: 21622848
references.citation: J Virol. 2007 Jul;81(14):7410-23
references.pmid: 17507479
references.citation: PLoS One. 2008 Aug 21;3(8):e2985
references.pmid: 18716658
references.citation: Nat Immunol. 2011 Jul 10;12(8):786-95
references.pmid: 21743478
references.citation: Am J Clin Pathol. 2010 Jul;134(1):27-35
references.pmid: 20551263
references.citation: N Engl J Med. 2003 May 15;348(20):1953-66
references.pmid: 12690092
references.citation: Bioinformatics. 2004 Jun 12;20(9):1464-5
references.pmid: 14962934
references.citation: Methods Mol Biol. 2009;541:1-22
references.pmid: 19381547
references.citation: Science. 1985 Mar 22;227(4693):1487-90
references.pmid: 4038818
references.citation: PLoS Pathog. 2008 Dec;4(12):e1000240
references.pmid: 19079579
references.citation: J Intensive Care Med. 2005 Jan-Feb;20(1):43-9
references.pmid: 15665259
references.citation: PLoS Pathog. 2008 Aug 01;4(8):e1000115
references.pmid: 18670648
references.citation: J Clin Invest. 1989 Aug;84(2):695-705
references.pmid: 2788176
references.citation: Respirology. 2003 Nov;8 Suppl:S6-8
references.pmid: 15018126
references.citation: Arch Dis Child. 1964 Jun;39:226-31
references.pmid: 14169450
references.citation: Am Rev Respir Dis. 1989 Aug;140(2):513-24
references.pmid: 2669580
references.citation: Am J Respir Cell Mol Biol. 2011 Nov;45(5):1015-21
references.pmid: 21617202
references.citation: Proc Am Thorac Soc. 2006 Jun;3(4):383-8
references.pmid: 16738205
references.citation: N Engl J Med. 2012 Nov 8;367(19):1814-20
references.pmid: 23075143
references.citation: Nat Rev Microbiol. 2010 Oct;8(10):717-29
references.pmid: 20805835
references.citation: J Clin Invest. 2011 Dec;121(12):4921-30
references.pmid: 22105170
references.citation: Thromb Haemost. 2008 Mar;99(3):494-501
references.pmid: 18327397
references.citation: Nat Immunol. 2009 Jan;10(1):116-125
references.pmid: 19029902
references.citation: J Pathol. 2003 Jul;200(3):282-9
references.pmid: 12845623
references.citation: Science. 2007 Jan 26;315(5811):509-13
references.pmid: 17255510
references.citation: Arch Pathol Lab Med. 1976 Mar;100(3):147-53
references.pmid: 946402
references.citation: BMC Genomics. 2009 Jul 20;10:327
references.pmid: 19619308
references.citation: Clin Infect Dis. 2004 May 15;38(10):1420-7
references.pmid: 15156481
references.citation: Thorax. 2005 May;60(5):401-9
references.pmid: 15860716
references.citation: J Chin Med Assoc. 2005 Jan;68(1):4-10
references.pmid: 15742856
references.citation: Respiration. 2005 May-Jun;72(3):263-9
references.pmid: 15942295
references.citation: BMC Syst Biol. 2007 Nov 21;1:54
references.pmid: 18031580
references.citation: Am J Respir Cell Mol Biol. 1996 Jan;14(1):53-60
references.pmid: 8534486
references.citation: Ann Pharmacother. 2011 Mar;45(3):364-71
references.pmid: 21386027
references.citation: PLoS Pathog. 2011 Jun;7(6):e1002099
references.pmid: 21731493
references.citation: Am J Physiol. 1999 Sep;277(3):L573-9
references.pmid: 10484465
references.citation: J Assoc Physicians India. 2011 Aug;59:498-500
references.pmid: 21887906
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Crit Care. 1998;2(1):29-34
references.pmid: 11056707
references.citation: PLoS Pathog. 2007 Aug 10;3(8):e112
references.pmid: 17696609
references.citation: PLoS Med. 2006 Dec;3(12):e525
references.pmid: 17194199
references.citation: PLoS Pathog. 2007 Jan;3(1):e5
references.pmid: 17222058
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L559-67
references.pmid: 19525387
references.citation: Bioinformatics. 2008 Mar 1;24(5):719-20
references.pmid: 18024473
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14040-5
references.pmid: 16169905
references.citation: Paediatr Respir Rev. 2001 Jun;2(2):151-8
references.pmid: 12531062
references.citation: Stat Appl Genet Mol Biol. 2005;4:Article17
references.pmid: 16646834
references.citation: PLoS Pathog. 2010 Apr 08;6(4):e1000849
references.pmid: 20386712
references.citation: Br J Haematol. 2005 May;129(3):307-21
references.pmid: 15842654
references.citation: BMC Bioinformatics. 2008 Dec 29;9:559
references.pmid: 19114008
references.citation: Clinics (Sao Paulo). 2006 Dec;61(6):497-502
references.pmid: 17187083
references.citation: Am J Pathol. 2005 Nov;167(5):1221-9
references.pmid: 16251407
references.citation: N Engl J Med. 2010 May 6;362(18):1708-19
references.pmid: 20445182
references.citation: Lancet. 2003 May 24;361(9371):1773-8
references.pmid: 12781536
references.citation: Thromb Haemost. 2006 Jul;96(1):100-1
references.pmid: 16807662