Identification of essential genes and receptors for the signaling of TLR2-dependent bacterial virulence factors (lipopeptides, peptidoglycan and lipoteichoic acid)

先天免疫系统对细菌毒力因子的识别是建立足够的免疫反应的第一步，最终将清除宿主的入侵病原体。这种识别的分子基础最近才开始被理解。革兰氏阴性和革兰氏阳性细菌细胞壁的成分，如脂多糖(LPS)、脂肽/脂蛋白(LP)、肽聚糖(PG)和脂磷壁酸(LTA)是非常有效的天然免疫反应激活剂。它们的主要靶细胞是单核细胞，其中一些成分的主要宿主识别是通过CD14介导的。然而，最近的数据显示，内毒素和LP/PG/LTA介导的信号受体和信号通路存在明显的差异。内毒素反应细胞表达Toll样受体(TLR)4，而LP/PG/LTA需要表达TLR2。此外，正在出现的数据明显有利于细菌病原体与多聚体受体复合体的结合。本项目将重点研究依赖TLR2的细菌毒力因子LP/PG/LTA的识别和信号转导。本项目的目标是：1)鉴定与LP/PG/LTA信号转导有关的未知基因；2)分析介导LP/PG/LTA识别的受体复合体。

The recognition of bacterial virulence factors by the innate immune system is the first step in mounting an adequate immune response that eventually will clear the host from the invading pathogen. The molecular basis for this recognition has just recently started to be understood. Components of Gram-negative and -positive bacteria cell walls, such as lipopolysaccharides (LPS), lipopeptides/lipoproteins (LP), peptidoglycan (PG), and lipoteichoic acid (LTA) are very potent activators of innate immune responses. Their main target cells are monocytes and the primary host recognition of some of these components is mediated through CD14. However, recent data show obvious differences between the mediating signaling receptors and pathways of LPS and LP/PG/LTA. Whereas LPS-responsive cells express Toll-like receptor (TLR) 4, LP/PG/LTA require the expression of TLR2. Furthermore, data are emerging that clearly favor the engagement of multimeric receptor complexes by bacterial pathogens. This project will focus on investigating the recognition and signaling of the TLR2-dependent bacterial virulence factors LP/PG/LTA. The aims of this project are 1) the identification and characterization of so far unknown genes that are essential for the signaling of LP/PG/LTA and 2) the analysis of the receptor complexes mediating LP/PG/LTA recognition.