细胞自噬调控Th17分化对耐甲氧西林金黄色葡萄球菌性脓毒症(sepsis) 的保护作用研究

Methicillin-resistant staphylococcus aureus (MRSA)-induced sepsis is a common cause of intensive care units with a high mortality. Autophagy participates in CD4+ T cell differentiation, and Th17 immune response is particularly important in the defense against MRSA infection. Whether autophagy has a protective effect on MRSA-induced sepsis is controversial. Whether or not autophagy affects MRSA-induced sepsis by affecting Th17 differentiation has not been investigated worldwide. Our preliminary study found that MRSA infection enhanced the expression of autophagy (increased LC3II/I, decreased P62), while rapamycin, a autophagy inducer, reduced tissue inflammation, decreased the expressions of Th17 cells and IL-17 cytokines, and improved survival rate of mice with MRSA-induced sepsis. Therefore, we speculate that autophagy could protect MRSA-induced sepsis via regulating Th17 differentiation, but the causal relationship between them and the underlying mechanisms are largely unclear. Using autophagy knockout mice (LC3B-/-) in this study, we will investigate the related mechanisms of autophagy in regulating Th17 differentiation and the exact role of autophagy in MRSA-induced sepsis through a series of in vitro and in vivo experiments, aiming at providing some theoretical support and experimental basis by targeting at autophagy as a non-antibiotic strategy to prevent and treat MRSA-induced sepsis.

耐甲氧西林金黄色葡萄球菌(MRSA)诱导的脓毒症是重症监护室的常见病因，死亡率高。细胞自噬参与CD4+T细胞分化，而Th17免疫应答在防御MRSA感染中尤为重要。细胞自噬对MRSA性脓毒症是否有保护作用还有争议。关于细胞自噬是否通过影响Th17分化进而保护MRSA性脓毒症，目前国内外没有这样的研究。我们前期研究发现MRSA感染导致细胞自噬表达增强 (LC3Ⅱ/Ⅰ增高，P62降低)，给予雷帕霉素(自噬增强剂)减轻MRSA性脓毒症小鼠组织炎症，降低Th17细胞和IL-17，改善生存率。因此，我们推测自噬可通过调节Th17分化进而保护MRSA性脓毒症，但其中因果关系以及内在机制不清楚。本课题将利用细胞自噬基因敲除小鼠(LC3B-/-)，通过体内外实验，探讨“细胞自噬调节Th17分化以及对MRSA性脓毒症的作用机制”，为靶向细胞自噬防治MRSA性脓毒症这种非抗生素策略提供一定的理论支持和实验依据。

耐甲氧西林金黄色葡萄球菌(MRSA)诱导的脓毒症是重症监护室的常见病因，死亡率高。目前发现胞自噬参与CD4+T细胞分化，而Th17免疫应答在防御MRSA感染中尤为重要。因此，我们推测自噬可通过调节Th17分化进而保护MRSA性脓毒症， 但其中因果关系以及内在机制不清楚。本项目主要研究内容和结果如下：(1) 发现自噬对 MRSA 性脓毒症具有脏器保护作用并改善小鼠生存率；(2) 自噬能够下调MRSA对 CD4+T细胞向Th17的分化，提示自噬对 MRSA性脓毒症的这种保护作用与其抑制Th17 细胞分化相关；(3) 自噬不减少 MRSA 性sepsis各脏器菌落数，提示这种保护作用与是否降低菌落数无关，也提示不具有抑制细菌作用。这些研究表明：细胞自噬对MRSA性脓毒症具有保护作用，而这种作用与其抑制 Th17分化，降低炎症风暴（降低炎症因子和炎症细胞）诱导的脏器损伤相关。 本研究的科学意义：(1) 细胞自噬对MRSA性脓毒症具有保护作用，而这种作用与其抑制 Th17分化和降低炎症风暴诱导的脏器损伤相关。(2) 本研究结果为 “靶向细胞自噬和Th17分化途径可以干预MRSA性重症感染”提供一定的科学依据和理论基础，同时也为“革兰氏阳性菌(尤其是MRSA)性脓毒症的非抗生素防治”提供一种新的科研思维和潜在防治策略。