Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology
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- Volume 39, pages 529–539 (2017)
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Abstract
Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.
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Masters PS, Perlman, S (2013) Coronaviridae. In: Knipe DM, Howley P (eds) Fields Virology. Lippincott Williams and Wilkins, Philadelphia, PA, pp 825–858
Siddell SZJ, Snijder EJ (2005) Coronaviruses, toroviruses, and arteriviruses, vol. 1. Hodder Arnold, London
Peck KM et al (2015) Coronavirus host range expansion and Middle East respiratory syndrome coronavirus emergence: biochemical mechanisms and evolutionary perspectives. Annu Rev Virol 2(1):95–117
Su S et al (2016) Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 24(6):490–502
Weiss SR, Navas-Martin S (2005) Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 69(4):635–664
Heugel J et al (2007) Coronavirus-associated pneumonia in previously healthy children. Pediatr Infect Dis J 26(8):753–755
Kuypers J et al (2007) Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics 119(1):e70–e76
Drosten C et al (2003) Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348(20):1967–1976
Kuiken T et al (2003) Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 362(9380):263–270
Peiris JS et al (2003) Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361(9366):1319–1325
van Boheemen S et al (2012) Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3(6)
Zaki AM et al (2012) Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367(19):1814–1820
Perlman S, Netland J (2009) Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7(6):439–450
WHO Cumulative number of reported probable cases of SARS. In: 2003
http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_RA_20140613.pdf WUoM-CTfAtHaIRfA-RGLaoMAf
WHO: Middle East respiratory syndrome coronavirus (MERS-CoV). http://www.who.int/emergencies/mers-cov/en/
Adney DR et al (2014) Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis 20(12):1999–2005
Alagaili AN et al (2014) Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia. MBio 5(2):e00884–e00814
Ge XY et al (2013) Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503(7477):535–538
Menachery VD et al (2015) A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med 21(12):1508–1513
Arabi YM et al (2014) Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med 160(6):389–397
Assiri A et al (2013) Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis 13(9):752–761
Leong HN et al (2006) Clinical and laboratory findings of SARS in Singapore. Ann Acad Med Singap 35(5):332–339
Saad M et al (2014) Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia. Int J Infect Dis 29:301–306
Al-Tawfiq JA et al (2014) Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients. Clin Infect Dis 59(2):160–165
Zumla A et al (2015) Middle East respiratory syndrome. Lancet 386(9997):995–1007
Peiris JS et al (2004) Severe acute respiratory syndrome. Nat Med 10(12 Suppl):S88–S97
Peiris JS et al (2003) Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361(9371):1767–1772
Nicholls J et al (2003) SARS: clinical virology and pathogenesis. Respirology 8(Suppl):S6–S8
van den Brand JM et al (2014) The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models. J Comp Pathol 151(1):83–112
Gu J et al (2005) Multiple organ infection and the pathogenesis of SARS. J Exp Med 202(3):415–424
Nicholls JM et al (2003) Lung pathology of fatal severe acute respiratory syndrome. Lancet 361(9371):1773–1778
van den Brand JM et al (2014) The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models. J Comp Pathol 151(1):83–112
Cui W et al (2003) Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome. Clin Infect Dis 37(6):857–859
Li T et al (2004) Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 189(4):648–651
Wang YH et al (2004) A cluster of patients with severe acute respiratory syndrome in a chest ward in southern Taiwan. Intensive Care Med 30(6):1228–1231
Ng DL et al (2016) Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014. Am J Pathol 186(3):652–658
Channappanavar R et al (2016) Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe 19(2):181–193
Davidson S et al (2015) Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interf Cytokine Res 35(4):252–264
Shaw AC et al (2013) Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13(12):875–887
Cheung CY et al (2005) Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J Virol 79(12):7819–7826
Law HK et al (2005) Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood 106(7):2366–2374
Yen YT et al (2006) Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro. J Virol 80(6):2684–2693
Chien JY et al (2006) Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 11(6):715–722
Wang CH et al (2005) Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res 6:42
Wong CK et al (2004) Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 136(1):95–103
Zhang Y et al (2004) Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 72(8):4410–4415
Cameron MJ et al (2008) Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus Res 133(1):13–19
Cameron MJRL, Xu L, Danesh A, Bermejo-Martin JF, Cameron CM, Muller MP, Gold WL, Richardson SE, Poutanen SM, Willey BM, DeVries ME, Fang Y, Seneviratne C, Bosinger SE, Persad D, Keshavjee S, Louie M, Loeb MB, Brunton J, McGeer AJ, Kelvin DJ (2007) Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol 81(16):8692–8706
Huang KJ et al (2005) An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 75(2):185–194
Theron M et al (2005) A probable role for IFN-gamma in the development of a lung immunopathology in SARS. Cytokine 32(1):30–38
Lau SK et al (2013) Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 94(Pt 12):2679–2690
Chu H et al (2015) Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis 213(6):904–14
Tynell J et al (2016) Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J Gen Virol 97(2):344–355
Zhou J et al (2014) Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis 209(9):1331–1342
Scheuplein VA et al (2015) High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus. J Virol 89(7):3859–3869
Kim ES et al (2016) Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 31(11):1717–1725
Min CK et al (2016) Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 6:25359
Roberts A et al (2005) Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans. J Virol 79(9):5833–5838
Day CW et al (2009) A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology 395(2):210–222
Nagata N et al (2008) Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice. Am J Pathol 172(6):1625–1637
Roberts A et al (2007) A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice. PLoS Pathog 3(1):e5
Frieman MB et al (2010) SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6(4):e1000849
Zhao J et al (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(12):4921–4930
Graham RL et al (2012) A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease. Nat Med 18(12):1820–1826
Rockx B et al (2009) Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol 83(14):7062–7074
Smits SL et al (2010) Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathog 6(2):e1000756
Totura AL et al (2015) Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. MBio 6(3):e00638–e00615
Jimenez-Guardeno JM et al (2014) The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. PLoS Pathog 10(8):e1004320
Nieto-Torres JL et al (2014) Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathog 10(5):e1004077
Nieto-Torres JL et al (2015) Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 485:330–339
de Wit E et al (2013) Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci U S A 110(41):16598–16603
Haagmans BL et al (2015) Asymptomatic Middle East respiratory syndrome coronavirus infection in rabbits. J Virol 89(11):6131–6135
Houser KV et al (2016) Prophylaxis with a Middle East respiratory syndrome coronavirus (MERS-CoV)-specific human monoclonal antibody protects rabbits from MERS-CoV infection. J Infect Dis 213(10):1557–1561
Falzarano D et al (2014) Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog 10(8):e1004250
Johnson RF et al (2015) Intratracheal exposure of common marmosets to MERS-CoV Jordan-n3/2012 or MERS-CoV EMC/2012 isolates does not result in lethal disease. Virology 485:422–430
Barlan A et al (2014) Receptor variation and susceptibility to Middle East respiratory syndrome coronavirus infection. J Virol 88(9):4953–4961
Zhao J et al (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111(13):4970–4975
Gretebeck LM, Subbarao K (2015) Animal models for SARS and MERS coronaviruses. Curr Opin Virol 13:123–129
van Doremalen N, Munster VJ (2015) Animal models of Middle East respiratory syndrome coronavirus infection. Antivir Res 122:28–38
Pascal KE et al (2015) Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. Proc Natl Acad Sci U S A 112(28):8738–8743
Cockrell A et al (2016) A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nature Microbiology 2:16226
Li K et al (2017) Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proceedings of the National Academy of Sciences 114(15):E3119–E3128
Frieman M et al (2007) Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J Virol 81(18):9812–9824
Kindler E et al (2016) Interaction of SARS and MERS coronaviruses with the antiviral interferon response. Adv Virus Res 96:219–243
Narayanan K et al (2008) Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells. J Virol 82(9):4471–4479
Sun L et al (2012) Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS One 7(2):e30802
Thiel V, Weber F (2008) Interferon and cytokine responses to SARS-coronavirus infection. Cytokine Growth Factor Rev 19(2):121–132
Totura AL, Baric RS (2012) SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Current Opinion in Virology 2(3):264–275
Wathelet MG et al (2007) Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol 81(21):11620–11633
Fehr AR et al (2016) The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. mBio 7(6):e01721–16
Frieman M et al (2009) Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol 83(13):6689–6705
Kopecky-Bromberg SA et al (2007) Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J Virol 81(2):548–557
Lu XL et al (2011) SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFN-beta induction pathway, and its C-terminal region is critical for the antagonism. Virus Genes 42(1):37–45
Siu KL et al (2014) Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain. Cell Mol Immunol 11(2):141–149
Lui PY et al (2016) Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3. Emerg Microbes Infect 5:e39
Yang Y et al (2013) The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell 4(12):951–961
Chu CM et al (2004) Initial viral load and the outcomes of SARS. CMAJ 171(11):1349–1352
Ng ML et al (2003) Proliferative growth of SARS coronavirus in Vero E6 cells. J Gen Virol 84(Pt 12):3291–3303
Oh MD et al (2016) Viral load kinetics of MERS coronavirus infection. N Engl J Med 375(13):1303–1305
Herold S et al (2008) Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med 205(13):3065–3077
Hogner K et al (2013) Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. PLoS Pathog 9(2):e1003188
Rodrigue-Gervais IG et al (2014) Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival. Cell Host Microbe 15(1):23–35
Zhao J et al (2010) T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice. J Virol 84(18):9318–9325
Kim KD et al (2007) Adaptive immune cells temper initial innate responses. Nat Med 13(10):1248–1252
Palm NW, Medzhitov R (2007) Not so fast: adaptive suppression of innate immunity. Nat Med 13(10):1142–1144
Zornetzer GA et al (2010) Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection. J Virol 84(21):11297–11309
Page C et al (2012) Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection. J Virol 86(24):13334–13349
Gralinski LE et al (2015) Genome wide identification of SARS-CoV susceptibility loci using the collaborative cross. PLoS Genet 11(10):e1005504
Drosten C et al (2013) Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis 13(9):745–751
Lew TW et al (2003) Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 290(3):374–380
Jiang Y et al (2005) Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 171(8):850–857
Reghunathan R et al (2005) Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunology 6:2
Stockman LJ et al (2006) SARS: systematic review of treatment effects. PLoS Med 3(9):e343
Al-Tawfiq JA et al (2014) Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 20:42–46
Falzarano D et al (2013) Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 19(10):1313–1317
Omrani AS et al (2014) Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 14(11):1090–1095
Auyeung TW et al (2005) The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. J Infect 51(2):98–102
Ho JC et al (2003) High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am J Respir Crit Care Med 168(12):1449–1456
Yam LY et al (2007) Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. J Infect 54(1):28–39
Haagmans BL et al (2004) Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 10(3):290–293
Zumla A et al (2016) Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 15(5):327–47
Davidson S et al (2016) IFNlambda is a potent anti-influenza therapeutic without the inflammatory side effects of IFNalpha treatment. EMBO Mol Med 8(9):1099–1112
Blazek K et al (2015) IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1beta production. J Exp Med 212(6):845–853
Imai Y et al (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133(2):235–249
Shirey KA et al (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497(7450):498–502
Teijaro JR et al (2011) Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146(6):980–991
Walsh KB et al (2011) Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc Natl Acad Sci U S A 108(29):12018–12023
Leuschner F et al (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36(23):1478–1488
Leuschner F et al (2011) Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 29(11):1005–1010
Darwish I et al (2011) Immunomodulatory therapy for severe influenza. Expert Rev Anti-Infect Ther 9(7):807–822
McDermott JE et al (2016) The effect of inhibition of PP1 and TNFalpha signaling on pathogenesis of SARS coronavirus. BMC Syst Biol 10(1):93
Acknowledgements
We thank Dr. Anthony Fehr for careful review of this manuscript. This work was supported in part by grants from the N.I.H. (PO1 AI060699, RO1 AI091322).
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This article is a contribution to the special issue on Cytokine Storm in Infectious Diseases - Guest Editor: John Teijaro
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Channappanavar, R., Perlman, S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 39, 529–539 (2017). https://doi.org/10.1007/s00281-017-0629-x
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DOI: https://doi.org/10.1007/s00281-017-0629-x
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