继发感染造成的组织器官损伤大大增加了脓毒症晚期患者的死亡风险。继发感染时，粒细胞免疫反应过度活化是造成组织损伤的重要原因之一。新近发现，天然免疫细胞具有“免疫训练”效应，能对初次病原刺激产生记忆，再次遇到病原时免疫反应增强。申请人前期研究发现，粒细胞免疫训练是导致二次感染时器官炎性损伤的主要机制；更为重要的是，糖代谢磷酸戊糖途径增强是粒细胞免疫训练的独特特征。据此提出：Akt1/mTOR/c-Myc通路激活磷酸戊糖途径，调控粒细胞免疫训练，在二次感染时过度活化，引起组织损伤。本项目拟采用脓毒症二次感染小鼠模型，明确粒细胞免疫训练在组织损伤中的作用；通过体内、体外实验阐明磷酸戊糖途径调控粒细胞免疫训练的机制；采用mTOR功能缺陷小鼠，探讨Akt/mTOR通路对磷酸戊糖途径和免疫训练的调控机制。从代谢途径和信号通路两个层面明确粒细胞免疫训练的机制，为减轻脓毒症二次感染组织损伤提供新的治疗靶点。

Tissue damage caused by the secondary infection greatly increased the risk of death of terminal patients with sepsis. In the secondary infection, the overactive immune response of neutrophils is one of the leading cause of tissue damage. Recently, scientists found that the innate immune cells can be “immune trained” by the first encounterment of pathogen and get memory. This effect strengthens the innate immune cells to response more intensively in the secondary infection. Previously, we have found that the immune trained neutrophils caused inflammatory damage of tissue during the secondary infection of sepsis; more importantly, the enhanced pentose-phophate pathway (PPP) of glucose metabolism is the unique features of trained neutrophils. We hypothesized that the PPP is activated by Akt1/mTOR/c-Myc signaling pathway and regulates neutrophil training, which leading to an overactivation of immune system and tissue damage in the secondary infection of sepsis. We aim to clarify the function of neutrophil training in tissue damage with the CLP-LPS secondary infection model, to illustrate the regulatory mechanisms of PPP on neutrophil training in vivo and in vitro, and to explore the regulatory mechanisms of Akt/mTOR pathway on PPP. Our program will illuminate the mechanism of neutrophil immune training in the levels of metabolic pathway and signaling pathway, and will provide new target for alleviate the immune injury caused by the secondary infection of sepsis.