CD44在艰难梭菌感染免疫炎症反应中的作用及机制研究

Clostridium difficile is identified as the major infectious cause in hospital. Cluster of differentiation 44 (CD44) plays a crucial role in innate and adaptive immune responses, and participates in host defense against various pathogenic microorganisms. However, the function and mechanism of CD44 in mediating the immune inflammatory response during Clostridium difficile infection (CDI) has not been revealed. Our previous study indicated CD44 was increased in the colon tissue of the CDI mouse model with more severe inflammatory damage than the normal control. The phagocytosis of macrophages was impaired after the down regulation of CD44. In the current study, we will collect the specimen from CDI patients and design the in vitro co-culture system of intestinal epithelial cells and macrophages, as well as the in vivo CDI mouse model. Based on these models, we intend to study the function of CD44 in regulating the immune inflammatory response during CDI. Furthermore, we will explore the mechanisms of CD44 in mediating the biological functions of macrophages and intestinal epithelial cells during CDI, including adhesion, phagocytosis, macrophage polarization (M1/2), inflammatory signaling pathways, and etc. Our study is of great significance on illustration of the mechanism of CD44 in enhancing the immune inflammation status of CDI patients. The study findings will provide new therapeutic methods for CDI through targeting the function of immune cells and related cytokines.

艰难梭菌是导致院内感染性腹泻的首要病因，CD44作为固有和适应性免疫应答的重要参与者，影响着机体防御多种病原微生物的感染免疫进程，但CD44促进艰难梭菌感染引发的过激炎症反应的作用及机制尚不清楚。我们前期研究发现艰难梭菌感染小鼠结肠组织CD44表达水平高于正常对照组，同时伴随着严重的结肠炎症损伤；CD44表达下调后，巨噬细胞吞噬功能减弱。本项目拟从临床标本，巨噬细胞/肠上皮细胞共培养模型和艰难梭菌感染动物模型的角度，研究CD44在艰难梭菌感染引发的免疫炎症反应中的作用；进一步探索CD44如何影响艰难梭菌感染的重要参与者巨噬细胞的黏附吞噬、M1/2表型极化等生物学功能；同时探究CD44参与调控艰难梭菌感染另一重要参与者肠上皮细胞的凋亡/坏死、炎症信号通路等分子机制。本研究将为阐明CD44促进艰难梭菌感染中免疫炎症反应作用及分子机制提供实验依据，并为艰难梭菌感染免疫炎症调控的治疗提供新靶点。

艰难梭菌感染是目前全球抗生素相关腹泻和肠胃炎相关死亡的主要原因。肠道炎症反应严重程度影响着艰难梭菌的感染进程。CD44影响着机体防御多种病原微生物的感染免疫进程，但CD44参与艰难梭菌感染引发的过激炎症反应的作用及机制尚不清楚。本项目探讨了CD44在艰难梭菌感染免疫炎症反应中的作用及机制。我们的研究结果提示，CD44促进了艰难梭菌感染的过激免疫炎症反应。CD44表达水平下调，缓解了艰难梭菌感染症状，包括降低肠道免疫炎症及损伤程度，减弱巨噬细胞的吞噬功能，改变巨噬细胞的极化状态，以抗炎型的M2表型为主。艰难梭菌重要毒力因子TcdB诱导肠上皮细胞中靶基因CDC45及MCM家族成员表达水平明显下调。本研究为阐明CD44促进艰难梭菌感染中免疫炎症反应作用及分子机制提供实验依据，并为艰难梭菌感染的治疗提供新靶点。