The possible molecular mechanism of immune injury in the mice treated with severe acute respiratory syndrome-CoV spike protein_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YAO Guohua , YANG Xinyan ,  XU Jun

Guangzhou Institute of Respiratory Disease，First Affiliated Hospital，Guangzhou Medical College.Guangzhou，Guangdong，510120，ChinaCorresponding author：XU Jun，E-mail：xufeili@vip.163.com;

Corresponding author：

XU Jun, Email: xufeili@vip.163.com

Keywords：

Severe acute respiratory syndrome; Coronavirus; Spike protein; Interferon-γ inducible protein 10

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To explore the immunopathologic mechanism underlying the inflammatory response after severe acute respiratory syndrome（SARS） invasion.Methods Pathway focused cDNA microarrays were employed for comparision of the gene expression patterns in 16HBEs treated with interferon-γ(IFN-γ) or the S protein of SARS-CoV.The S proteins were administered to BALB/c mice and the pathological changes of lung and spleen were observed.Results S protein activated JAK/STAT signal pathway in the 16HBEs with inducible protein 10（IP-10） gene expression，and the specific inhibitors of the JAK/STAT signal pathway were able to downregulate the induction of IP-10.The mice instilled intracheally with S proteins revealed obvious acute diffuse damage and increased IP-10 expression and CD68+ macrophages infiltration in both lung and spleen tissues.In contrast，the treatment with JAK3 inhibitors attenuated lung and spleen injury in the mice.Conclusion Our findings support that the activation of JAK/STAT pathway induced by SARS-CoV S protein plays a key role in promotion of an IFN -γ inducible chemokine cascade，which can help in the development of novel drug and therapeutics for prevention and treatment of SARS.

Citation： YAO Guohua,YANG Xinyan,XU Jun. The possible molecular mechanism of immune injury in the mice treated with severe acute respiratory syndrome-CoV spike protein. Chinese Journal of Respiratory and Critical Care Medicine, 2008, 08(2): 81-87. doi: Copy

1.	Ksiazek TG ， Erdman D ， Goldsmith CS ，et al.A novel coronavirus associated with severe acute respiratory syndrome.N Engl J Med，2003，348：1953-1966.
2.	Wong RS，Wu A，To K，et al.Haematological manifestations in patients with severe acute respiratory syndrome：retrospective analysis.BMJ，2003，326：1358-1362.
3.	Ding Y，Wang H，Shen H，et al.The clinical pathology of severe acute respiratory syndrome (SARS)：a report from China.J Pathol，2003，200：282-289.
4.	Lang ZW，Zhang LJ，Zhang S，et al.A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology，2003，35：526-531.
5.	郑则广，陈荣昌，黎毅敏，等.严重急性呼吸综合征患者继发下呼吸道感染的队列分析.中国呼吸与危重监护杂志，2003，2：270-274.
6.	Xu J，Zhong S，Liu J，et al.Detection of severe acute respiratory syndrome coronavirus in the brain：potential role of the chemokine mig in pathogenesis.Clin Infect Dis，2005，41：1089-1096.
7.	Jiang Y ， Xu J ， Zhou C ，et al.Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.Am J Respir Crit Care Med，2005，171：850-857.
8.	Tomura K，Narumi S.Differential induction of interferon (IFN)-inducible protein 10 following differentiation of a monocyte，macrophage cell lineage is related to the changes of nuclear proteins bound to IFN stimulus response element and kappaB sites.Int J Mol Med，1999，3：477-484.
9.	Vockerodt M，Pinkert D，Smola-Hess S，et al.The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10：importance of mRNA half-life regulation.Int J Cancer，2005，114：598-605.
10.	Dufour JH，Dziejman M，Liu MT，et al.IFN-g Inducible Protein 10 (IP-10；CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking.J Immunol，2002，168：3195-3204.
11.	Liu MT，Keirstead HS，Lane TE.Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.J Immunol，2001，167：4091-4097.
12.	Rota PA，Oberste MS，Monroe SS，et al.Characterization of a novel coronavirus associated with severe acute respiratory syndrome.Science，2003，300：1394-1399.
13.	Wang YD，Sin WY，Xu GB，et al.T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T-cell immune response in patients who recover from SARS.J Virol，2004，78：5612-5618.
14.	要国华，杨新艳，徐军.严重急性呼吸综合征冠状病毒S蛋白启动急性肺损伤的可能机制.医学研究生学报，2005，18：677-681.
15.	李志杰，要国华，刘靖华，等.SARS冠状病毒S蛋白在昆虫细胞中的表达和纯化.病毒学报，2005，21：303-304.
16.	Darnell JE，Kerr IM，Sark GM，et al.Jak-STAT pathways and transcriptional activation in response to IFNs and other extracelluar signaling proteins.Science，1994，264：1415-1421.
17.	Hogan RJ ， Gao G ， Rowe T ，et al.Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1.J Virol，2004，78：11416-11421.
18.	Lambert E ， Boudot C ， Kadri Z ，et al.Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival.Biochem J，2003，372：767-774.
19.	Christen U ， Benke D ， Wolfe T ，et al.Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient.J Clin Invest，2004，113：74-84.
20.	Glass WG ， Subbarao K ， Murphy B ，et al.Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice.J Immunol，2004，173：4030-4039.
21.	Liu MT ， Keirstead HS ， Lane TE ，et al.Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.J Immunol，2001，167：4091-4097.
22.	Sohn SJ ， Forbush KA ， Nguyen N ，et al.Requirement for Jak3 in mature T cells：its role in regulation of T cell homeostasis.J Immunol，1998，160：2130-2138.
23.	Vincenti F.mmunosuppression minimization：current and future trends in transplant immunosuppression.J Am Soc Nephrol，2003，14：1940-1948.
24.	Adams C ， Aldous DJ ， Amendola S ，et al.Mapping the kinase domain of janus kinase 3.Bioorg Med Chem Lett，2003，13：3105-3110.
25.	Changelian PS ， Flanagan ME ， Ball DJ ，et al.Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.Science，2003，302：875-878.
26.	Chen RC，Tang XP，Tan SY，et al.Treatment of severe acute respiratory syndrome with glucosteroids：the Guangzhou experience.Chest，2006，129：1441-1452.

1. Ksiazek TG ， Erdman D ， Goldsmith CS ，et al.A novel coronavirus associated with severe acute respiratory syndrome.N Engl J Med，2003，348：1953-1966.
2. Wong RS，Wu A，To K，et al.Haematological manifestations in patients with severe acute respiratory syndrome：retrospective analysis.BMJ，2003，326：1358-1362.
3. Ding Y，Wang H，Shen H，et al.The clinical pathology of severe acute respiratory syndrome (SARS)：a report from China.J Pathol，2003，200：282-289.
4. Lang ZW，Zhang LJ，Zhang S，et al.A clinicopathological study of three cases of severe acute respiratory syndrome (SARS).Pathology，2003，35：526-531.
5. 郑则广，陈荣昌，黎毅敏，等.严重急性呼吸综合征患者继发下呼吸道感染的队列分析.中国呼吸与危重监护杂志，2003，2：270-274.
6. Xu J，Zhong S，Liu J，et al.Detection of severe acute respiratory syndrome coronavirus in the brain：potential role of the chemokine mig in pathogenesis.Clin Infect Dis，2005，41：1089-1096.
7. Jiang Y ， Xu J ， Zhou C ，et al.Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.Am J Respir Crit Care Med，2005，171：850-857.
8. Tomura K，Narumi S.Differential induction of interferon (IFN)-inducible protein 10 following differentiation of a monocyte，macrophage cell lineage is related to the changes of nuclear proteins bound to IFN stimulus response element and kappaB sites.Int J Mol Med，1999，3：477-484.
9. Vockerodt M，Pinkert D，Smola-Hess S，et al.The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10：importance of mRNA half-life regulation.Int J Cancer，2005，114：598-605.
10. Dufour JH，Dziejman M，Liu MT，et al.IFN-g Inducible Protein 10 (IP-10；CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking.J Immunol，2002，168：3195-3204.
11. Liu MT，Keirstead HS，Lane TE.Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.J Immunol，2001，167：4091-4097.
12. Rota PA，Oberste MS，Monroe SS，et al.Characterization of a novel coronavirus associated with severe acute respiratory syndrome.Science，2003，300：1394-1399.
13. Wang YD，Sin WY，Xu GB，et al.T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus spike protein elicit a specific T-cell immune response in patients who recover from SARS.J Virol，2004，78：5612-5618.
14. 要国华，杨新艳，徐军.严重急性呼吸综合征冠状病毒S蛋白启动急性肺损伤的可能机制.医学研究生学报，2005，18：677-681.
15. 李志杰，要国华，刘靖华，等.SARS冠状病毒S蛋白在昆虫细胞中的表达和纯化.病毒学报，2005，21：303-304.
16. Darnell JE，Kerr IM，Sark GM，et al.Jak-STAT pathways and transcriptional activation in response to IFNs and other extracelluar signaling proteins.Science，1994，264：1415-1421.
17. Hogan RJ ， Gao G ， Rowe T ，et al.Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1.J Virol，2004，78：11416-11421.
18. Lambert E ， Boudot C ， Kadri Z ，et al.Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival.Biochem J，2003，372：767-774.
19. Christen U ， Benke D ， Wolfe T ，et al.Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient.J Clin Invest，2004，113：74-84.
20. Glass WG ， Subbarao K ， Murphy B ，et al.Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice.J Immunol，2004，173：4030-4039.
21. Liu MT ， Keirstead HS ， Lane TE ，et al.Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis.J Immunol，2001，167：4091-4097.
22. Sohn SJ ， Forbush KA ， Nguyen N ，et al.Requirement for Jak3 in mature T cells：its role in regulation of T cell homeostasis.J Immunol，1998，160：2130-2138.
23. Vincenti F.mmunosuppression minimization：current and future trends in transplant immunosuppression.J Am Soc Nephrol，2003，14：1940-1948.
24. Adams C ， Aldous DJ ， Amendola S ，et al.Mapping the kinase domain of janus kinase 3.Bioorg Med Chem Lett，2003，13：3105-3110.
25. Changelian PS ， Flanagan ME ， Ball DJ ，et al.Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.Science，2003，302：875-878.
26. Chen RC，Tang XP，Tan SY，et al.Treatment of severe acute respiratory syndrome with glucosteroids：the Guangzhou experience.Chest，2006，129：1441-1452.

Previous Article
Relationship of ECG and Troponin I with Acute Coronary Syndrome
Next Article
Changes of Bone on X-ray Photography in Preschool Children in Kashin-Beck Disease Endemic Area

Chinese Journal of Respiratory and Critical Care Medicine

The possible molecular mechanism of immune injury in the mice treated with severe acute respiratory syndrome-CoV spike protein

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content