GSDME介导的细胞焦亡在肠道病毒71型感染致病机制中的作用研究

肠道病毒71型是引起重症手足口病的主要病原体，可导致严重的神经系统并发症，但其致病机制仍不清楚。本课题组前期报道了EV71感染能够激活NLRP3炎性小体，病毒编码的3C和2A反过来抑制NLRP3炎性小体的激活，同时其编码的3C蛋白可以切割GSDMD，破坏其诱导细胞焦亡的N端片段。但是我们发现病毒感染仍可以诱导细胞焦亡，并检测到GSDME的切割，提示GSDME可能在EV71的致病中起着重要作用。报道表明，GSDME介导的细胞凋亡至焦亡的转换在化疗药物引起的正常组织的损伤、免疫力下降中起着重要作用，但在病毒诱导的疾病中的作用未见报道。鉴此，本研究以EV71诱导的细胞焦亡为切入点，进一步分析EV71诱导细胞焦亡的分子机制，并利用GSDME基因敲除的动物检测其在EV71致病中的关键作用及机理。这将首次阐明GSDME介导的细胞焦亡在病毒感染致病中的作用及分子机制，为手足口病的防治提供科学依据。

Enterovirus 71 (EV71) is the main cause of severe hand, foot and mouth disease (HFMD), which can lead to severe neurological complications. However, the pathogenesis of EV71 infection is still unclear. Our previous study reported that EV71 infection can activate NLRP3 inflammasome, and in turn inhibit NLRP3 inflammasome through its 3C and 2A proteases. At the same time, the 3C protein encoded by EV71 can cleave GSDMD and destroy the N-terminal fragment-induced cell pyroptosis. However, we found that viral infection can still induce cell pyroptosis and the cleavage of GSDME, suggesting that GSDME may play critical roles in the pathogenesis of EV71. Recently, it has been reported that GSDME-mediated cell death from apoptosis to pyroptosis transition plays an important role in the damage of normal tissues caused by chemotherapeutic drugs, but the role of GSDME in virus-induced diseases has not been reported. Therefore, this study further analyzed the molecular mechanism of EV71-induced pyropotis, and used GSDME gene knockout animals to detect the key role of pyroptosis in EV71 pathogenesis and its mechanism. It will be the first time to elucidate the role and molecular mechanism of GDME-mediated pyroptosis in the pathogenesis of viral infection, and provide scientific basis for the prevention and treatment of hand, foot and mouth disease.