严重急性呼吸综合征冠状病毒Spike蛋白诱发小鼠免疫损伤的实验研究  

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

作　　者：要国华[1] 杨新艳[1] 徐军[1] 

机构地区：[1]广州医学院第一附属医院广州呼吸疾病研究所,广东广州510120

出　　处：《中国呼吸与危重监护杂志》2008年第2期81-87,161,162,共9页Chinese Journal of Respiratory and Critical Care Medicine

基　　金：国家自然科学基金资助项目(编号:30340029)

摘　　要：目的研究严重急性呼吸综合征冠状病毒(SARS-CoV)的Spike蛋白(S蛋白)引起免疫病理损伤的分子机制。方法采用信号转导通路发现者基因芯片筛选相关诱导免疫炎症的信号转导通路基因的表达,通过RT-PCR对基因芯片筛选基因进一步验证并观察信号分子阻断剂干预的影响;将SARS-CoV的S蛋白及信号分子阻断剂分别经气管滴注、尾静脉注射的途径感染BALB/c小鼠,通过免疫组织化学观察肺及免疫器官的病理变化。结果S蛋白诱导了与γ干扰素(IFN-γ)类似的JAK-STAT的信号通路相关基因的表达,RT-PCR证实S蛋白诱导了人支气管上皮细胞的γ干扰素诱导蛋白10(IP-10)基因表达,该作用能够被JAK3抑制剂完全阻断。经气管滴注或尾静脉注射S蛋白均可引起小鼠肺损伤和脾脏损伤。JAK3抑制剂能够抑制S蛋白诱导小鼠肺内IP-10表达,减轻病理损伤。结论JAK-STAT信号转导通路的激活可能在SARS-CoV的S蛋白诱导的以IP-10为代表的炎症级联中起重要作用,该发现可为发展抗SARS病毒诱导的免疫损伤治疗提供新的策略。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 spike protein of SARS-CoV. The spike proteins were administered to BALB/c mice and the pathological changes of lung and spleen were observed. Results Spike 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 spike 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. Condusion Our findings support that the activation of JAK/STAT pathway induced by SARS-CoV spike 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.

关 键 词：严重急性呼吸综合征 冠状病毒 SPIKE蛋白 γ干扰素诱导蛋白10 

分 类 号：R511.9[医药卫生—内科学]