Cofilin分子在高毒力肺炎克雷伯杆菌抗中性粒细胞吞噬中的作用机制研究

Generally, hypervirulent Klebsiella pneunoniae (hvKP) infected healthy adults, and characterized with high virulence, anti-phagocytosis, and blood stream spread. The resistance of hvKP to Polymorphonuclear neutrophils (PMN) phagocytosis is the basis of the high virulence and blood stream spread. However, the immunological mechanisms of hvKP resisting PMN phagocytosis and escape from killing by innate immune system are not well understood. The role of PMN phagocytosis requires the participation of actin, and cofilin is the key molecule to regulate the activity of actin. The preliminary study results of our project team showed that hvKP infection could decrease the function of migration, activity of actin and cofilin in PMN. In addition, the mRNA level of CLEcsf8 in PMN was reduced after hvKP infection. Therefore, a scientific hypothesis was proposed: hvKP interacts with the CLEcsf8 receptor, expression on the surface of PMN, and regulates the cofilin-related signaling pathway to reduce the activation of intracellular actin, thus preventing PMN from playing its normal phagocytotic function. By doing so, the hvKP can escape the killing of the innate immune system of and spread by blood stream. Firstly, PMN function and actin activation status after hvKP infection were discussed. Secondly, the mechanism of cofilin participating in hvKP anti-phagocytosis process was explored. Finally, the role of CLEcsf8 receptor was explored. This project provides experimental basis and theoretical basis for the establishment of new strategies to promote the innate immune system to kill hvKP effectively .

高毒力肺炎克雷伯杆菌（hvKP）多感染健康成年人，具有高毒力、抗吞噬、易血流播散等特点，而抗吞噬特性是其发挥高毒力和进行血流播散的基础，但其免疫学相关机制不甚清楚。肌动蛋白是多形核中性粒细胞（PMN）发挥噬菌作用所必需的，而cofilin是调节其活性的关键分子。前期结果显示：hvKP感染可降低PMN的迁移，以及actin和cofilin活性，同时还降低CLEcsf8受体的mRNA水平。由此提出科学假说：hvKP通过与PMN表面CLEcsf8作用，抑制cofilin相关的信号通路使胞内肌动蛋白活化降低，PMN吞噬功能受损，从而得以逃避天然免疫的杀伤。本项目首先对hvKP感染后PMN功能以及肌动蛋白活化状态进行探讨；其次，探究cofilin参与hvKP抗吞噬过程的机制；最后，探索CLEcsf8受体在其中的作用。本项目为建立促进机体免疫系统有效杀伤hvKP的新策略提供实验依据和理论基础。

本项目在高毒力肺炎克雷伯杆菌（hvKP）具有高毒力、抗吞噬、易血流，但其免疫学相关机制不甚清楚的背景下，通过对hvKP感染后PMN功能以及肌动蛋白相关调控因子cofilin等作用进行实验探究。本项目结果显示：hvKP通过与PMN表面CLEcsf8和CXCR3受体作用，抑制cofilin相关的信号通路使胞内肌动蛋白活化降低，通过CXCR3-LIMK-cofilin-actin信号通路，使PMN趋化和吞噬功能受损，从而得以逃避天然免疫的杀伤。本项目为建立促进机体免疫系统有效杀伤hvKP的新策略提供实验依据和理论基础。