Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury
Lisa E Gralinski, Armand Bankhead 3rd, 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, Lisa E Gralinski, Armand Bankhead 3rd, 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
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.
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References
- Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ. 2003. A novel coronavirus associated with severe acute respiratory syndrome. N. Engl. J. Med. 348:1953–1966
- Lau SK, Woo PC, Li KS, Huang Y, Tsoi HW, Wong BH, Wong SS, Leung SY, Chan KH, Yuen KY. 2005. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. USA 102:14040–14045
- Christian MD, Poutanen SM, Loutfy MR, Muller MP, Low DE. 2004. Severe acute respiratory syndrome. Clin. Infect. Dis. 38:1420–1427
- Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N. Engl. J. Med. 367:1814–1820
- Franks TJ, Chong PY, Chui P, Galvin JR, Lourens RM, Reid AH, Selbs E, McEvoy CP, Hayden CD, Fukuoka J, Taubenberger JK, Travis WD. 2003. Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Hum. Pathol. 34:743–748
- Hwang DM, Chamberlain DW, Poutanen SM, Low DE, Asa SL, Butany J. 2005. Pulmonary pathology of severe acute respiratory syndrome in Toronto. Mod. Pathol. 18:1–10
- Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS. 2003. Lung pathology of fatal severe acute respiratory syndrome. Lancet 361:1773–1778
- Nicholls J, Dong XP, Jiang G, Peiris M. 2003. SARS: clinical virology and pathogenesis. Respirology 8(Suppl):S6–S8
- Hui DS, Joynt GM, Wong KT, Gomersall CD, Li TS, Antonio G, Ko FW, Chan MC, Chan DP, Tong MW, Rainer TH, Ahuja AT, Cockram CS, Sung JJ. 2005. Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors. Thorax 60:401–409
- Ebbert JO, Limper AH. 2005. Respiratory syncytial virus pneumonitis in immunocompromised adults: clinical features and outcome. Respiration 72:263–269
- Harms PW, Schmidt LA, Smith LB, Newton DW, Pletneva MA, Walters LL, Tomlins SA, Fisher-Hubbard A, Napolitano LM, Park PK, Blaivas M, Fantone J, Myers JL, Jentzen JM. 2010. Autopsy findings in eight patients with fatal H1N1 influenza. Am. J. Clin. Pathol. 134:27–35
- Liem NT, Nakajima N, Phat LP, Sato Y, Thach HN, Hung PV, San LT, Katano H, Kumasaka T, Oka T, Kawachi S, Matsushita T, Sata T, Kudo K, Suzuki K. 2008. H5N1-infected cells in lung with diffuse alveolar damage in exudative phase from a fatal case in Vietnam. Jpn. J. Infect. Dis. 61:157–160
- Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM, Zaki SR, Hayden FG, Hui DS, Kettner JD, Kumar A, Lim M, Shindo N, Penn C, Nicholson KG. Clinical aspects of pandemic 200 influenza A (H1N1) virus infection. N. Engl. J. Med. 362:1708–1719
- Hoste EA, Roosens CD, Bracke S, Decruyenaere JM, Benoit DD, Vandewoude KH, Colardyn FA. 2005. Acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome. J. Intensive Care Med. 20:43–49
- De Smet R, Marchal K. 2010. Advantages and limitations of current network inference methods. Nat. Rev. Microbiol. 8:717–729
- Langfelder P, Horvath S. 2007. Eigengene networks for studying the relationships between co-expression modules. BMC Syst. Biol 1:54.10.1186/1752-0509-1-S1-P54
- Langfelder P, Zhang B, Horvath S. 2008. Defining clusters from a hierarchical cluster tree: the Dynamic tree cut package for R. Bioinformatics 24:719–720
- Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS. 2006. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc. Natl. Acad. Sci. U. S. A. 103:17402–17407
- Mariño-Ramírez L, Tharakaraman K, Bodenreider O, Spouge J, Landsman D. 2009. Identification of cis-regulatory elements in gene co-expression networks using A-GLAM. Methods Mol. Biol. 541:1–22
- Mason MJ, Fan G, Plath K, Zhou Q, Horvath S. 2009. Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells. BMC Genomics 10:327.10.1186/1471-2164-10-327
- Zhang B, Horvath S. 2005. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4:Article17.10.2202/1544-6115.1128
- Roberts A, Deming D, Paddock CD, Cheng A, Yount B, Vogel L, Herman BD, Sheahan T, Heise M, Genrich GL, Zaki SR, Baric R, Subbarao K. 2007. A mouse adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog. 3:e5.10.1371/journal.ppat.0030005
- Hattori N, Sisson TH, Xu Y, Desai TJ, Simon RH. 1999. Participation of urokinase-type plasminogen activator receptor in the clearance of fibrin from the lung. Am. J. Physiol. 277:L573–L579
- Pardo A, Selman M. 2006. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc. Am. Thorac. Soc. 3:383–388
- Hatcher MA, Starr JA. 2011. Role of tissue plasminogen activator in acute ischemic stroke. Ann. Pharmacother. 45:364–371
- Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. 2003. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J. Pathol. 200:282–289
- Rockx B, Sheahan T, Donaldson E, Harkema J, Sims AC, Heise M, Pickles RJ, Cameron M, Kelvin D, Baric RS. 2007. Synthetic reconstruction of zoonotic and early human SARS-CoV isolates that produce fatal disease in aged mice. J. Virol. 81:7410–7412
- Langfelder P, Horvath S. 2008. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559.10.1186/1471-2105-9-559
- Van De Craen B, Declerck PJ, Gils A. 2012. The biochemistry, physiology and pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb. Res. 130:576–585
- Nassar T, Yarovoi S, Fanne RA, Waked O, Allen TC, Idell S, Cines DB, Higazi AA. 2011. Urokinase plasminogen activator regulates pulmonary arterial contractility and vascular permeability in mice. Am. J. Respir. Cell Mol. Biol. 45:1015–1021
- Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS. 1989. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J. Clin. Invest. 84:695–705
- Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P. 2008. Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases. Thromb. Haemost. 99:494–501
- Cesarman-Maus G, Hajjar KA. 2005. Molecular mechanisms of fibrinolysis. Br. J. Haematol. 129:307–321
- Gajl-Peczalska K. 1964. Plasma protein composition of hyaline membrane in the newborn as studies by immunofluorescence. Arch. Dis. Child. 39:226–231
- Peres e Serra A, Parra ER, Eher E, Capelozzi VL. 2006. Nonhomogeneous immunostaining of hyaline membranes in different manifestations of diffuse alveolar damage. Clinics (Sao Paulo) 61:497–502
- Mallory GB., Jr. 2001. Surfactant proteins: role in lung physiology and disease in early life. Paediatr. Respir. Rev. 2:151–158
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U. S. A. 102:15545–15550
- Beissbarth T, Speed TP. 2004. GOstat: find statistically overrepresented gene ontologies within a group of genes. Bioinformatics 20:1464–1465
- Frieman MB, Chen J, Morrison TE, Whitmore A, Funkhouser W, Ward JM, Lamirande EW, Roberts A, Heise M, Subbarao K, Baric RS. 2010. SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog. 6:e1000849.10.1371/journal.ppat.1000849
- Sheahan T, Morrison TE, Funkhouser W, Uematsu S, Akira S, Baric RS, Heise MT. 2008. MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog. 4:e1000240.10.1371/journal.ppat.1000240
- Zhao J, Zhao J, Legge K, Perlman S. 2011. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121:4921–4930
- Walters DM, Antao-Menezes A, Ingram JL, Rice AB, Nyska A, Tani Y, Kleeberger SR, Bonner JC. 2005. Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis. Am. J. Pathol. 167:1221–1229
- Chen CY, Lee CH, Liu CY, Wang JH, Wang LM, Perng RP. 2005. Clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome. J. Chin. Med. Assoc. 68:4–10
- Yu H, Gao Z, Feng Z, Shu Y, Xiang N, Zhou L, Huai Y, Feng L, Peng Z, Li Z, Xu C, Li J, Hu C, Li Q, Xu X, Liu X, Liu Z, Xu L, Chen Y, Luo H, Wei L, Zhang X, Xin J, Guo J, Wang Q, Yuan Z, Zhang K, Zhang W, Yang J, Zhong X, Xia S, Li L, Cheng J, Ma E, He P, Lee SS, Wang Y, Uyeki TM, Yang W, Yang W. 2008. Clinical characteristics of 26 human cases of highly pathogenic avian influenza A (H5N1) virus infection in China. PLoS One 3:e2985.10.1371/journal.pone.0002985
- Reynolds HN, McCunn M, Borg U, Habashi N, Cottingham C, Bar-Lavi Y. 1998. Acute respiratory distress syndrome: estimated incidence and mortality rate in a 5 million-person population base. Crit. Care 2:29–34
- Tatebe K, Zeytun A, Ribeiro RM, Hoffmann R, Harrod KS, Forst CV. 2010. Response network analysis of differential gene expression in human epithelial lung cells during avian influenza infections. BMC Bioinformatics 11:170.10.1186/1471-2105-11-170
- van Riel D, Leijten LM, van der Eerden M, Hoogsteden HC, Boven LA, Lambrecht BN, Osterhaus AD, Kuiken T. 2011. Highly pathogenic avian influenza virus H5N1 infects alveolar macrophages without virus production or excessive TNF-alpha induction. PLoS Pathog. 7:e1002099.10.1371/journal.ppat.1002099
- Bruce SR, Atkins CL, Colasurdo GN, Alcorn JL. 2009. Respiratory syncytial virus infection alters surfactant protein A expression in human pulmonary epithelial cells by reducing translation efficiency. Am. J. Physiol. Lung Cell. Mol. Physiol. 297:L559–L567
- Stinson SF, Ryan DP, Hertweck S, Hardy JD, Hwang-Kow SY, Loosli CG. 1976. Epithelial and surfactant changes in influenzal pulmonary lesions. Arch. Pathol. Lab. Med. 100:147–153
- Burkhardt A. 1989. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am. Rev. Respir. Dis. 140:513–524
- Dang CV, Bell WR, Kaiser D, Wong A. 1985. Disorganization of cultured vascular endothelial cell monolayers by fibrinogen fragment D. Science 227:1487–1490
- Leavell KJ, Peterson MW, Gross TJ. 1996. The role of fibrin degradation products in neutrophil recruitment to the lung. Am. J. Respir. Cell Mol. Biol. 14:53–60
- Zmijewski JW, Bae HB, Deshane JS, Peterson CB, Chaplin DD, Abraham E. 2011. Inhibition of neutrophil apoptosis by PAI-1. Am. J. Physiol. Lung Cell. Mol. Physiol. 301:L247–L254
- Perrone LA, Plowden JK, García-Sastre A, Katz JM, Tumpey TM. 2008. H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice. PLoS Pathog. 4:e1000115.10.1371/journal.ppat.1000115
- de Lang A, Baas T, Teal T, Leijten LM, Rain B, Osterhaus AD, Haagmans BL, Katze MG. 2007. Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques. PLoS Pathog. 3:e112.10.1371/journal.ppat.0030112
- Wu YP, Wei R, Liu ZH, Chen B, Lisman T, Ren DL, Han JJ, Xia ZL, Zhang FS, Xu WB, Preissner KT, de Groot PG. 2006. Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients. Thromb. Haemost. 96:100–101
- Prasad HB, Puranik SC, Kadam DB, Sangle SA, Borse RT, Basavraj A, Umarji PB, Mave V, Ghorpade SV, Bharadwaj R, Jamkar AV, Mishra AC. 2011. Retrospective analysis of necropsy findings in patients of H1N1 and their correlation to clinical features. J. Assoc. Physicians India 59:498–500
- Lim JH, Jono H, Komatsu K, Woo CH, Lee J, Miyata M, Matsuno T, Xu X, Huang Y, Zhang W, Park SH, Kim YI, Choi YD, Shen H, Heo KS, Xu H, Bourne P, Koga T, Yan C, Wang B, Chen LF, Feng XH, Li JD. 2012. CYLD negatively regulates transforming growth factor-beta-signalling via deubiquitinating Akt. Nat. Commun. 3:771.10.1038/ncomms1776
- Lathem WW, Price PA, Miller VL, Goldman WE. 2007. A plasminogen-activating protease specifically controls the development of primary pneumonic plague. Science 315:509–513
- Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B. 2011. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 12:786–795
- Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, Pirani A, Gernert K, Deng J, Marzolf B, Kennedy K, Wu H, Bennouna S, Oluoch H, Miller J, Vencio RZ, Mulligan M, Aderem A, Ahmed R, Pulendran B. 2008. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat. Immunol. 10:116–125
- Deming D, Sheahan T, Heise M, Yount B, Davis N, Sims A, Suthar M, Harkema J, Whitmore A, Pickles R, West A, Donaldson E, Curtis K, Johnston R, Baric R. 2006. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med. 3:e525.10.1371/journal.pmed.0030525
- Benjamini Y, Yekutieli D. 2001. The control of the false discovery rate in multiple testing under dependency. Ann. Stat. 29:1165–1188
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