Molecular mechanisms of Toll-like receptor 9 activation and the role of TLRs in autoimmunity

先天免疫系统已经开发出种系编码模式识别受体（PRR），促进对微生物病原体的快速反应。toll样受体（TLRs）是一个新发现的脊椎动物PRR家族，通过识别保守的病原体相关分子模式（PAMP）来激活和指导抗病原体反应。TLR2和TLR4是对革兰氏阳性和革兰氏阴性细菌细胞壁成分（如脂多糖（LPS）或肽聚糖）的反应受体。TLR9最近被鉴定为细菌DNA的受体，其作用类似于LPS的PAMP。与LPS或肽聚糖不同，细菌DNA必须被未知序列的非特异性DNA受体吸收并内吞才能激活信号通路。TLR9定位于内体/溶酶小泡结构中，未发表的数据表明，一种未知的伴侣蛋白负责将新合成的TLR9转运到这个小泡结构中。本项目的目的是鉴定TLR9的相关蛋白，使其能够识别CpG-DNA。这些共受体的鉴定和功能表征，包括在小鼠中的敲除研究，将有助于了解对细菌DNA识别至关重要的分子机制，并深入了解先天免疫系统的抗病原体反应。

The innate immune system has developed germ-line encoded pattern recognition receptors (PRR) that promote rapid responses to microbial pathogens. Toll-like receptors (TLRs) represent a newly recognized family of vertebrate PRR that activate and direct the anti-pathogen response through recognition of conserved pathogen associated molecular patterns (PAMP). TLR2 and TLR4 are the receptors for responses to gram-positive and gram-negative bacterial cell wall components such as lipopolysaccharide (LPS) or peptidoglycan. TLR9 has recently been identified as receptor for bacterial DNA, which acts as PAMP, similar to LPS. In contrast to LPS or peptidoglycan, bacterial DNA has to be taken up by an unknown sequence unspecific DNA receptor and endocytozed to activate the signaling pathway. TLR9 is localized in an endosomal / lysosmal vesicular structure and unpublished data suggest an unknown chaperone being responsible for the transport of newly synthesized TLR9 into this compartment. Aim of this project is to identify associated proteins of TLR9 which allow recognition of CpG-DNA. The identification and functional characterization of those co-receptors including knock-out studies in mice will help to understand the molecular mechanisms which are important for recognition of bacterial DNA and give insight into the anti pathogen response of the innate immune system.