Role of the C-type lectin receptor CLEC12A in Legionella pneumophila infection

嗜肺军团菌是人类肺炎的重要病因。它感染被细菌劫持的肺泡巨噬细胞，在细菌效应分子的帮助下作为复制生态位。然而，肺泡巨噬细胞和宿主通常能够感知感染并清除它，而不会造成过度的组织损伤。本项目拟重点研究c型凝集素受体（CLRs）参与嗜肺乳杆菌免疫应答调控的假说。初步数据表明，CLR CLEC12A识别嗜肺乳杆菌，在体外积极影响感染巨噬细胞的早期抗菌防御，并下调细胞因子的产生。基于这些初步的结果，我们的目标是：1)确定CLEC12A的细菌配体；2)研究CLEC12A对巨噬细胞信号转导、细胞内防御和嗜肺乳杆菌诱导的细胞因子产生的影响；3)体内分析CLEC12A在嗜肺乳杆菌肺炎中的作用；4)确定cle12a在人类细胞和军团病患者样本中的功能。

Legionella pneumophila is an important cause of pneumonia in humans. It infects alveolar macrophages that are hijacked by the bacterium with the help of bacterial effector molecules to serve as replication niche. However, alveolar macrophages and the host are usually able to sense the infection and clear it without excessive tissue damage. The proposed project focuses on the hypothesis that C-type lectin receptors (CLRs) contribute to the regulation of the immune response against L. pneumophila. Prelimary data indicate that the CLR CLEC12A recognizes L. pneumophila, impacts the early antibacterial defense in infected macrophages in vitro positively, and down-regulates cytokine production. Based on these initial results, we aim at 1) identifying the bacterial ligand of CLEC12A; 2) investigating the impact of CLEC12A on signal transduction, intracellular defense in macrophages and L. pneumophila-induced cytokine production; 3) analyzing the role of CLEC12A in L. pneumophila pneumonia in vivo; and 4) characterizing the function of CLEC12A in human cells and samples derived from Legionnaires’ disease patients.