How the SARS coronavirus causes disease: host or organism?

The previous epidemic of severe acute respiratory syndrome (SARS) has ended. However, many questions concerning how the aetiological agent, the novel SARS coronavirus (CoV), causes illness in humans remain unanswered. The pathology of fatal cases of SARS is dominated by diffuse alveolar damage. Specific histological changes are not detected in other organs. These contrast remarkably with the clinical picture, in which there are apparent manifestations in multiple organs. Both pathogen and host factors are important in the pathogenesis of SARS. The choice of specific receptors and the unique genome of the SARS‐CoV are important elements in understanding the biology of the pathogen. For the host cells, the outcome of SARS‐CoV infection, whether there are cytopathic effects or not, depends on the cell types that are infected. At the whole‐body level, immune‐mediated damage, due to activation of cytokines and/or chemokines and, perhaps, autoimmunity, may play key roles in the clinical and pathological features of SARS. Continued research is still required to determine the pathogenetic mechanisms involved and to combat this new emerging human infectious disease. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  W. Hong,et al.  Characterization of a Unique Group-Specific Protein (U122) of the Severe Acute Respiratory Syndrome Coronavirus , 2004, Journal of Virology.

[2]  S. Asa,et al.  Pulmonary pathology of severe acute respiratory syndrome in Toronto , 2005, Modern Pathology.

[3]  Obi L. Griffith,et al.  The Genome Sequence of the SARS-Associated Coronavirus , 2003, Science.

[4]  A. Kanamaru,et al.  Common features in the onset of ARDS after administration of granulocyte colony-stimulating factor. , 2002, Chest.

[5]  Jens H. Kuhn,et al.  Retroviruses Pseudotyped with the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Efficiently Infect Cells Expressing Angiotensin-Converting Enzyme 2 , 2004, Journal of Virology.

[6]  W. Hong,et al.  The Severe Acute Respiratory Syndrome Coronavirus 3a Protein Up-Regulates Expression of Fibrinogen in Lung Epithelial Cells , 2005, Journal of Virology.

[7]  S. Humphries,et al.  Genetic polymorphisms associated with susceptibility and outcome in ARDS. , 2002, Chest.

[8]  D. Dimitrov,et al.  The SARS-CoV S glycoprotein: expression and functional characterization , 2003, Biochemical and Biophysical Research Communications.

[9]  Hong Yang,et al.  Long-term SARS Coronavirus Excretion from Patient Cohort, China , 2004, Emerging infectious diseases.

[10]  John L. Sullivan,et al.  Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus , 2003, Nature.

[11]  K. Subbarao,et al.  pH-Dependent Entry of Severe Acute Respiratory Syndrome Coronavirus Is Mediated by the Spike Glycoprotein and Enhanced by Dendritic Cell Transfer through DC-SIGN , 2004, Journal of Virology.

[12]  T. Greenough,et al.  Efficient Replication of Severe Acute Respiratory Syndrome Coronavirus in Mouse Cells Is Limited by Murine Angiotensin-Converting Enzyme 2 , 2004, Journal of Virology.

[13]  R. Chiu,et al.  Molecular epidemiology of SARS--from Amoy Gardens to Taiwan. , 2003, The New England journal of medicine.

[14]  Larissa B. Thackray,et al.  CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  W. Marasco,et al.  An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus , 2005, The Journal of pathology.

[16]  F. Lai,et al.  Acute renal impairment in coronavirus-associated severe acute respiratory syndrome , 2005, Kidney International.

[17]  G. Meduri,et al.  Infections and the inflammatory response in acute respiratory distress syndrome. , 1997, Chest.

[18]  Peter Cameron,et al.  A major outbreak of severe acute respiratory syndrome in Hong Kong. , 2003, The New England journal of medicine.

[19]  C. Hsiao,et al.  Clinicopathology of severe acute respiratory syndrome: an autopsy case report. , 2004, Journal of the Formosan Medical Association = Taiwan yi zhi.

[20]  J. Sung,et al.  The 3a protein of severe acute respiratory syndrome-associated coronavirus induces apoptosis in Vero E6 cells. , 2005, The Journal of general virology.

[21]  R. Crystal,et al.  Macaque Model for Severe Acute Respiratory Syndrome , 2004, Journal of Virology.

[22]  Wenhui Li,et al.  A 193-Amino Acid Fragment of the SARS Coronavirus S Protein Efficiently Binds Angiotensin-converting Enzyme 2* , 2004, Journal of Biological Chemistry.

[23]  Ching-lung Lai,et al.  Temporal patterns of hepatic dysfunction and disease severity in patients with SARS. , 2003, JAMA.

[24]  D. Luk,et al.  Severe acute respiratory syndrome in children: Experience in a regional hospital in Hong Kong* , 2003, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[25]  C. Wong,et al.  Chemokine response in children with SARS , 2005, Archives of Disease in Childhood.

[26]  C. Johnston,et al.  ACE2, a new regulator of the renin–angiotensin system , 2004, Trends in Endocrinology & Metabolism.

[27]  S. Chollet-Martin,et al.  Polymorphonuclear neutrophil activation during the acute respiratory distress syndrome , 2000, Intensive Care Medicine.

[28]  F. Kirchhoff,et al.  LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus , 2005, Virology.

[29]  G. Fey,et al.  Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor , 2004, Biochemical and Biophysical Research Communications.

[30]  V. Chinchilli,et al.  Polymorphisms of human SP‐A, SP‐B, and SP‐D genes: association of SP‐B Thr131Ile with ARDS , 2000, Clinical genetics.

[31]  Junya Fukuoka,et al.  Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore , 2003, Human Pathology.

[32]  J. Sung,et al.  Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis , 2003, BMJ : British Medical Journal.

[33]  H. Rosenberg,et al.  Chemokine regulation of inflammation during acute viral infection , 2003, Current opinion in allergy and clinical immunology.

[34]  W. Hong,et al.  Overexpression of 7a, a Protein Specifically Encoded by the Severe Acute Respiratory Syndrome Coronavirus, Induces Apoptosis via a Caspase-Dependent Pathway , 2004, Journal of Virology.

[35]  C. Hsiao,et al.  Identification of a novel protein 3a from severe acute respiratory syndrome coronavirus , 2004, FEBS Letters.

[36]  J. Sung,et al.  Persistent infection of SARS coronavirus in colonic cells in vitro , 2004, Journal of medical virology.

[37]  Qingling Zhang,et al.  Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS‐CoV) in SARS patients: implications for pathogenesis and virus transmission pathways , 2004, The Journal of pathology.

[38]  Arthur S Slutsky,et al.  Angiotensin-converting enzyme 2 protects from severe acute lung failure , 2005, Nature.

[39]  Yi Guan,et al.  Lung pathology of fatal severe acute respiratory syndrome , 2003, The Lancet.

[40]  Kwok-Hung Chan,et al.  Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  G. Tse,et al.  Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in‐situ hybridization study of fatal cases , 2004, The Journal of pathology.

[42]  J. Sung,et al.  Early Enhanced Expression of Interferon-Inducible Protein-10 (CXCL-10) and Other Chemokines Predicts Adverse Outcome in Severe Acute Respiratory Syndrome , 2005, Clinical chemistry.

[43]  D. Hui,et al.  Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome , 2005, Journal of Clinical Virology.

[44]  T. Kirikae,et al.  Identification of an alternative 5′‐untranslated exon and new polymorphisms of angiotensin‐converting enzyme 2 gene: Lack of association with SARS in the Vietnamese population , 2005, American journal of medical genetics. Part A.

[45]  Y. Kooyk,et al.  DC-SIGN: escape mechanism for pathogens , 2003, Nature Reviews Immunology.

[46]  R. Rappuoli,et al.  SARS — beginning to understand a new virus , 2003, Nature Reviews Microbiology.

[47]  J. Sung,et al.  Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection , 2003, Gastroenterology.

[48]  W. Leung,et al.  Coronaviral hypothetical and structural proteins were found in the intestinal surface enterocytes and pneumocytes of severe acute respiratory syndrome (SARS) , 2005, Modern Pathology.

[49]  S. Moochhala,et al.  Chemokines in acute respiratory distress syndrome , 2005, American journal of physiology. Lung cellular and molecular physiology.

[50]  Xu Han-You,et al.  Acute Respiratory Syndrome (SARS) , 2004 .

[51]  Yao-Hsu Yang,et al.  Autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome (SARS)‐associated coronavirus infection , 2005, Journal of medical virology.

[52]  M. Burdick,et al.  Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection 1 , 2003, The Journal of Immunology.

[53]  Michel Theron,et al.  An interferon‐γ‐related cytokine storm in SARS patients† , 2004, Journal of medical virology.

[54]  J. Sung,et al.  Association of Human-Leukocyte-Antigen Class I (B*0703) and Class II (DRB1*0301) Genotypes with Susceptibility and Resistance to the Development of Severe Acute Respiratory Syndrome , 2004, The Journal of infectious diseases.

[55]  Xiaolei Yin,et al.  Highly infectious SARS-CoV pseudotyped virus reveals the cell tropism and its correlation with receptor expression , 2004, Biochemical and Biophysical Research Communications.

[56]  T. Menges,et al.  Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients , 2001, The Lancet.

[57]  G. Navis,et al.  Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis , 2004, The Journal of pathology.

[58]  S. Humphries,et al.  Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. , 2002, American journal of respiratory and critical care medicine.

[59]  P. Chan,et al.  Specific epitopes of the structural and hypothetical proteins elicit variable humoral responses in SARS patients , 2006, Journal of Clinical Pathology.

[60]  Michelle M. Packard,et al.  Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan , 2005, Human Pathology.

[61]  Malik Peiris,et al.  Koch's postulates fulfilled for SARS virus , 2003, Nature.

[62]  W. Hong,et al.  A Novel Severe Acute Respiratory Syndrome Coronavirus Protein, U274, Is Transported to the Cell Surface and Undergoes Endocytosis , 2004, Journal of Virology.

[63]  O. Tsang,et al.  Absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study , 2005, BMC infectious diseases.

[64]  J. Sung,et al.  Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome , 2004, Clinical and experimental immunology.

[65]  Ching-lung Lai,et al.  SARS‐associated viral hepatitis caused by a novel coronavirus: Report of three cases , 2004, Hepatology.

[66]  Z. Lang,et al.  A clinicopathological study of three cases of severe acute respiratory syndrome (SARS) , 2003, Pathology.

[67]  J. Peiris,et al.  Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome , 2003, The Lancet.

[68]  G. Bellingan The pulmonary physician in critical care • 6: The pathogenesis of ALI/ARDS , 2002, Thorax.

[69]  Albert D. M. E. Osterhaus,et al.  SARS virus infection of cats and ferrets , 2003, Nature.

[70]  Xin Li,et al.  The clinical pathology of severe acute respiratory syndrome (SARS): a report from China , 2003, The Journal of pathology.

[71]  A. Cariou,et al.  Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate* , 2002, Critical care medicine.

[72]  Jun Xu,et al.  Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. , 2005, American journal of respiratory and critical care medicine.

[73]  L. Trentin,et al.  CXC chemokines IP-10 and mig expression and direct migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis. , 2000, American journal of respiratory and critical care medicine.

[74]  W. Travis,et al.  Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. , 2004, Archives of pathology & laboratory medicine.

[75]  Y. Lau,et al.  Chemokine up-regulation in SARS-coronavirus–infected, monocyte-derived human dendritic cells , 2005, Blood.

[76]  W. Hong,et al.  The severe acute respiratory syndrome coronavirus 3a is a novel structural protein , 2005, Biochemical and Biophysical Research Communications.

[77]  Guoping Zhao,et al.  Molecular Evolution of the SARS Coronavirus During the Course of the SARS Epidemic in China , 2004, Science.

[78]  J. Villar,et al.  Genetic susceptibility to acute lung injury , 2003, Critical care medicine.

[79]  C. Ayata,et al.  Timing of neurologic deterioration in massive middle cerebral artery infarction: A multicenter review , 2003, Critical care medicine.

[80]  Ben Berkhout,et al.  Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[81]  K. Kain,et al.  Fatal Severe Acute Respiratory Syndrome Is Associated with Multiorgan Involvement by Coronavirus , 2005, The Journal of infectious diseases.

[82]  Sung Keun Kang,et al.  Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. , 2004, Science.

[83]  D. Hui,et al.  ACE2 Gene Polymorphisms Do Not Affect Outcome of Severe Acute Respiratory Syndrome , 2004, Clinical chemistry.

[84]  J. Dennis,et al.  Dynamic Changes in Clinical Features and Cytokine/Chemokine Responses in Sars Patients Treated with Interferon Alfacon-1 plus Corticosteroids , 2005, Antiviral therapy.

[85]  Christian Drosten,et al.  Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome , 2003, Science.

[86]  N. Nagata,et al.  Laboratory and Epidemiology Communications SARS Coronavirus-Infected Cells in Lung Detected by New In Situ Hybridization Technique , 2003 .

[87]  R. Sung,et al.  Pathology of fatal human infection associated with avian influenza A H5N1 virus , 2001, Journal of medical virology.

[88]  J. Sung,et al.  Retrospective analysis of liver function derangement in severe acute respiratory syndrome , 2004, The American Journal of Medicine.

[89]  Christl A. Donnelly,et al.  SARS-CoV Antibody Prevalence in All Hong Kong Patient Contacts , 2004, Emerging infectious diseases.

[90]  A. Steinkasserer,et al.  DC-SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the S Protein of Severe Acute Respiratory Syndrome Coronavirus , 2004, Journal of Virology.

[91]  Mark Chappell,et al.  A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury , 2005, Nature Medicine.

[92]  J. Loo,et al.  Association of HLA class I with severe acute respiratory syndrome coronavirus infection , 2003, BMC Medical Genetics.

[93]  C. Dolea,et al.  World Health Organization , 1949, International Organization.

[94]  Krishna Shankara Narayanan,et al.  Severe Acute Respiratory Syndrome Coronavirus 3a Protein Is a Viral Structural Protein , 2005, Journal of Virology.

[95]  D. Dimitrov,et al.  A model of the ACE2 structure and function as a SARS-CoV receptor , 2003, Biochemical and Biophysical Research Communications.

[96]  J. Chan,et al.  The spectrum of pathological changes in severe acute respiratory syndrome (SARS) , 2004, Histopathology.

[97]  T. Kirikae,et al.  ACE1 polymorphism and progression of SARS , 2004, Biochemical and Biophysical Research Communications.

[98]  S. Lai,et al.  Treatment of severe acute respiratory syndrome , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[99]  C. Biron,et al.  A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense. , 2000, The Journal of clinical investigation.

[100]  K. Wong,et al.  Myopathic changes associated with severe acute respiratory syndrome: a postmortem case series. , 2005, Archives of neurology.

[101]  J. Sung,et al.  Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS) , 2004, Journal of Clinical Pathology.

[102]  Y. Lau,et al.  Chemokine upregulation in SARS coronavirus infected human monocyte derived dendritic cells , 2008 .

[103]  Tzei-Yi Lin,et al.  Detection of Severe Acute Respiratory Syndrome–Associated Coronavirus in Pneumocytes of the Lung , 2004, American journal of clinical pathology.