肺炎克雷伯菌高毒力株（hvKP）是原发性肝脓肿的重要病原菌，常可并发脓毒症及迁徙性感染，严重威胁人类健康。中性粒细胞（PMN）凋亡延迟是影响脓毒症进展及预后的关键。课题组前期研究发现，hvKP可通过VI型分泌系统特异分泌Hcp1蛋白，以抑制PMN内Caspase-3的表达及活化，引发凋亡延迟。但Hcp1蛋白通过何种途径抑制Caspase-3的表达及活化，这一过程对hvKP脓毒症继发迁徙性感染及预后有何影响目前还不清楚。本项目拟在前期基础上，通过建立小鼠脓毒症继发迁徙性感染模型，利用Hcp1蛋白为切入点，以PMN凋亡延迟为主线，抓住Caspase-3凋亡通路的重要环节，分别在分子、细胞和动物水平探讨解析Hcp1蛋白调控PMN凋亡的机制，阐明Hcp1蛋白对hvKP脓毒症继发迁徙性感染过程及转归的影响，为寻找新型干预hvKP感染的药物靶标提供新思路。

Hypervirulent clinical variant of Klebsiella pneumoniae (hvKP) has been documented as the major pathogenic cause of pyogenic liver abscess, which often complicated by sepsis and metastatic infection and posed a serious health threat to human beings. Delayed neutrophil apoptosis is widely accepted to be associated with the progression and prognosis of sepsis. Our previous study demonstrated that the Hcp1 protein secreted by hvKP was a important effector of T6SS and could inhibit the expression and activation of caspase-3 to cause the delayed netrophil apotosis. However, which signaling pathway the Hcp1 protein use to inhibit the expression and activation of caspase-3, and how to affect the sepsis and the secondary metastatic infection and the prognosis by this process remain unclear. In this project, based on our previous study, we establish the murine model of sepsis secondary metastatic infection, choose the Hcp1 protein as the breakthrough point, set the delayed neutrophil apoptosis as the main line, and capture the important aspects of the caspase-3 apoptosis singaling pathway, in order to further demonstrate the mechanism of delayed neutrophil apoptosis regulated by the Hcp1 protein from the molecular, cellular and animal level and give us a further understanding for the effect of Hcp1 protein in septic metastatic infection and prognosis in sepsis. Hope, the research is expected to provide new insights into the exploration of new targets for the development of preventive or therapeutic drugs and/or vaccines against hvKP infection.