Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 5/2017

01-07-2017 | Review

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

Authors: Rudragouda Channappanavar, Stanley Perlman

Published in: Seminars in Immunopathology | Issue 5/2017

Login to get access

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.
Literature
1.
Masters PS, Perlman, S (2013) Coronaviridae. In: Knipe DM, Howley P (eds) Fields Virology. Lippincott Williams and Wilkins, Philadelphia, PA, pp 825–858
2.
Siddell SZJ, Snijder EJ (2005) Coronaviruses, toroviruses, and arteriviruses, vol. 1. Hodder Arnold, London
3.
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):95–117PubMedCrossRef
4.
Su S et al (2016) Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 24(6):490–502PubMedCrossRef
5.
Weiss SR, Navas-Martin S (2005) Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 69(4):635–664PubMedPubMedCentralCrossRef
6.
Heugel J et al (2007) Coronavirus-associated pneumonia in previously healthy children. Pediatr Infect Dis J 26(8):753–755PubMedCrossRef
7.
Kuypers J et al (2007) Clinical disease in children associated with newly described coronavirus subtypes. Pediatrics 119(1):e70–e76PubMedCrossRef
8.
Drosten C et al (2003) Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 348(20):1967–1976PubMedCrossRef
9.
Kuiken T et al (2003) Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 362(9380):263–270PubMedCrossRef
10.
Peiris JS et al (2003) Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361(9366):1319–1325PubMedCrossRef
11.
van Boheemen S et al (2012) Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3(6)
12.
Zaki AM et al (2012) Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367(19):1814–1820PubMedCrossRef
13.
14.
WHO Cumulative number of reported probable cases of SARS. In: 2003
15.
16.
17.
Adney DR et al (2014) Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis 20(12):1999–2005PubMedPubMedCentralCrossRef
18.
19.
20.
21.
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):389–397PubMedCrossRef
22.
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):752–761PubMedCrossRef
23.
Leong HN et al (2006) Clinical and laboratory findings of SARS in Singapore. Ann Acad Med Singap 35(5):332–339PubMed
24.
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 29:301–306PubMedCrossRef
25.
Al-Tawfiq JA et al (2014) Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients. Clin Infect Dis 59(2):160–165PubMedCrossRef
26.
27.
28.
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):1767–1772PubMedCrossRef
29.
30.
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):83–112PubMedCrossRef
31.
32.
Nicholls JM et al (2003) Lung pathology of fatal severe acute respiratory syndrome. Lancet 361(9371):1773–1778PubMedCrossRef
33.
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
34.
Cui W et al (2003) Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome. Clin Infect Dis 37(6):857–859PubMedCrossRef
35.
Li T et al (2004) Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 189(4):648–651PubMedCrossRef
36.
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):1228–1231PubMedCrossRef
37.
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):652–658PubMedCrossRef
38.
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):181–193PubMedPubMedCentralCrossRef
39.
Davidson S et al (2015) Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interf Cytokine Res 35(4):252–264CrossRef
40.
41.
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):7819–7826PubMedPubMedCentralCrossRef
42.
43.
44.
Chien JY et al (2006) Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 11(6):715–722PubMedCrossRef
45.
Wang CH et al (2005) Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir Res 6:42PubMedPubMedCentralCrossRef
46.
47.
48.
Cameron MJ et al (2008) Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus Res 133(1):13–19PubMedCrossRef
49.
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):8692–8706PubMedPubMedCentralCrossRef
50.
Huang KJ et al (2005) An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 75(2):185–194PubMedCrossRef
51.
Theron M et al (2005) A probable role for IFN-gamma in the development of a lung immunopathology in SARS. Cytokine 32(1):30–38PubMedCrossRef
52.
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):2679–2690PubMedCrossRef
53.
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
54.
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):344–355PubMedPubMedCentralCrossRef
55.
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):1331–1342PubMedCrossRef
56.
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):3859–3869PubMedPubMedCentralCrossRef
57.
Kim ES et al (2016) Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 31(11):1717–1725PubMedPubMedCentralCrossRef
58.
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 6:25359PubMedPubMedCentralCrossRef
59.
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):5833–5838PubMedPubMedCentralCrossRef
60.
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):210–222PubMedPubMedCentralCrossRef
61.
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):1625–1637PubMedPubMedCentralCrossRef
62.
63.
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):e1000849PubMedPubMedCentralCrossRef
64.
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):4921–4930PubMedPubMedCentralCrossRef
65.
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):1820–1826PubMedPubMedCentralCrossRef
66.
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):7062–7074PubMedPubMedCentralCrossRef
67.
68.
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–e00615PubMedPubMedCentralCrossRef
69.
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):e1004320PubMedPubMedCentralCrossRef
70.
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):e1004077PubMedPubMedCentralCrossRef
71.
Nieto-Torres JL et al (2015) Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 485:330–339PubMedPubMedCentralCrossRef
72.
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):16598–16603PubMedPubMedCentralCrossRef
73.
74.
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):1557–1561PubMedPubMedCentralCrossRef
75.
76.
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 485:422–430PubMedPubMedCentralCrossRef
77.
78.
79.
80.
81.
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):8738–8743PubMedPubMedCentralCrossRef
82.
Cockrell A et al (2016) A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nature Microbiology 2:16226
83.
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
84.
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):9812–9824PubMedPubMedCentralCrossRef
85.
Kindler E et al (2016) Interaction of SARS and MERS coronaviruses with the antiviral interferon response. Adv Virus Res 96:219–243PubMedCrossRef
86.
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):4471–4479PubMedPubMedCentralCrossRef
87.
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):e30802PubMedPubMedCentralCrossRef
88.
Thiel V, Weber F (2008) Interferon and cytokine responses to SARS-coronavirus infection. Cytokine Growth Factor Rev 19(2):121–132PubMedCrossRef
89.
Totura AL, Baric RS (2012) SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Current Opinion in Virology 2(3):264–275PubMedCrossRef
90.
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):11620–11633PubMedPubMedCentralCrossRef
91.
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
92.
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):6689–6705PubMedPubMedCentralCrossRef
93.
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):548–557PubMedCrossRef
94.
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):37–45PubMedCrossRef
95.
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):141–149PubMedPubMedCentralCrossRef
96.
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:e39PubMedPubMedCentralCrossRef
97.
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):951–961PubMedPubMedCentralCrossRef
98.
99.
Ng ML et al (2003) Proliferative growth of SARS coronavirus in Vero E6 cells. J Gen Virol 84(Pt 12):3291–3303PubMedCrossRef
100.
Oh MD et al (2016) Viral load kinetics of MERS coronavirus infection. N Engl J Med 375(13):1303–1305PubMedCrossRef
101.
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):3065–3077PubMedPubMedCentralCrossRef
102.
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):e1003188PubMedPubMedCentralCrossRef
103.
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):23–35PubMedCrossRef
104.
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):9318–9325PubMedPubMedCentralCrossRef
105.
106.
Palm NW, Medzhitov R (2007) Not so fast: adaptive suppression of innate immunity. Nat Med 13(10):1142–1144PubMedCrossRef
107.
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):11297–11309PubMedPubMedCentralCrossRef
108.
Page C et al (2012) Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection. J Virol 86(24):13334–13349PubMedPubMedCentralCrossRef
109.
110.
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):745–751PubMedCrossRef
111.
Lew TW et al (2003) Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 290(3):374–380PubMedCrossRef
112.
Jiang Y et al (2005) Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 171(8):850–857PubMedCrossRef
113.
Reghunathan R et al (2005) Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunology 6:2
114.
115.
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 20:42–46PubMedCrossRef
116.
Falzarano D et al (2013) Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 19(10):1313–1317PubMedPubMedCentralCrossRef
117.
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):1090–1095PubMedCrossRef
118.
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):98–102PubMedCrossRef
119.
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):1449–1456PubMedCrossRef
120.
Yam LY et al (2007) Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. J Infect 54(1):28–39PubMedCrossRef
121.
Haagmans BL et al (2004) Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 10(3):290–293PubMedCrossRef
122.
Zumla A et al (2016) Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 15(5):327–47
123.
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):1099–1112PubMedPubMedCentralCrossRef
124.
125.
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):235–249PubMedCrossRef
126.
127.
128.
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):12018–12023PubMedPubMedCentralCrossRef
129.
130.
131.
Darwish I et al (2011) Immunomodulatory therapy for severe influenza. Expert Rev Anti-Infect Ther 9(7):807–822PubMedCrossRef
132.
Metadata
Title
Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology
Authors
Rudragouda Channappanavar
Stanley Perlman
Publication date
01-07-2017
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 5/2017
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-017-0629-x

Other articles of this Issue 5/2017

Seminars in Immunopathology 5/2017 Go to the issue

Review

Immune-mediated cytokine storm and its role in severe dengue

Review

New fronts emerge in the influenza cytokine storm

Review

The meteorology of cytokine storms, and the clinical usefulness of this knowledge

Review

Molecular pathogenesis of viral hemorrhagic fever

Review

Cytokine storm and sepsis disease pathogenesis

Introduction

Cytokine storms in infectious diseases

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits