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应答的第一步，最终将宿主从入侵的病原体中清除。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组分，如脂多糖（LPS）、脂肽/脂蛋白（LP）、肽聚糖（PG）和脂磷壁酸（LTA）是先天免疫应答的非常有效的激活剂。它们的主要靶细胞是单核细胞，其中一些组分的主要宿主识别是通过CD 14介导的。然而，最近的数据表明，介导的信号受体和途径的LPS和LP/PG/LTA之间的明显差异。而LPS-应答细胞表达Toll样受体（TLR）4，LP/PG/LTA需要TLR 2的表达。此外，数据正在出现，明确有利于细菌病原体的多聚体受体复合物的参与。本项目将重点研究TLR 2依赖的细菌毒力因子LP/PG/LTA的识别和信号转导。本项目的目的是1）鉴定和表征迄今未知的对LP/PG/LTA信号传导至关重要的基因，2）分析介导LP/PG/LTA识别的受体复合物。

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.