Roles of Toll Like Receptors in Innate Immunity

描述(由申请人提供)：最近发现的同源基因 果蝇Toll受体蛋白引起了人们对确定其作用的兴趣 这些蛋白质的先天免疫力。果蝇相关蛋白Toll和Toll 18-Wheeler是抗真菌和抗细菌反应所必需的 飞。人类基因组编码至少10个不同的Toll样受体(TLR) 蛋白质基因虽然在体内的功能在很大程度上是未知的。一直以来 提出巨噬细胞可能利用TLR蛋白作为其 对细菌病原体的反应。在小鼠中，单个TLR的突变 基因导致对革兰氏阴性菌的反应性降低 体外和体内。我们已经发现，缺乏TLR4功能的小鼠高度 与正常小鼠相比，容易受到致命性分枝杆菌感染。我们 最近用整体表征了巨噬细胞依赖TLR的激活 分枝杆菌和几种纯化的细菌细胞壁成分。这些研究 已经表明不同的细菌产物通过不同的TLR激活细胞 蛋白质和不同的TLR激动剂可以诱导不同的模式 细胞因子的产生。与细胞对革兰氏阴性细菌的反应不同， 结核分枝杆菌对TLR依赖的细胞激活不会 需要CD14。结核分枝杆菌活菌在体外可激活巨噬细胞 通过TLR2或TLR4。与细胞有关的分枝杆菌配体 通过不同的TLR依赖的通路激活已经被发现，但 没有生化特征的。这个项目的长期目标 是表征TLR依赖的信号，并定义这些 信号在激发巨噬细胞的先天免疫反应中发挥作用。的目标是 这一建议是为了(1)确定不同的TLR蛋白是否相互作用 激活共享和不同的信号转导通路，(2)确定 如果不同的TLR蛋白参与激活不同的功能反应 以及(3)确定TLR功能的选择性丧失 会导致先天免疫力的改变。

DESCRIPTION (provided by the applicant): The recent discovery of homologues of the Drosophila Toll receptor protein has elicited interest in defining the role of these proteins in innate immunity. The related Drosophila proteins Toll and 18-Wheeler are required for anti-fungal and anit-bacterial responses in the fly. The human genome encodes at least 10 distinct Toll-like receptor (TLR) protein genes although their functions in vivo are largely unknown. It has been proposed that macrophages are likely to utilize TLR proteins as part of their responses against bacterial pathogens. In mice, the mutation in a single TLR gene results in diminished responsiveness to Gram-negative bacteria both in vitro and in vivo. We have found that mice lacking functional TLR4 are highly susceptible to lethal mycobacterial infection, compared with normal mice. We recently characterized the TLR-dependent activation of macrophages by whole mycobacteria and several purified bacterial cell wall components. These studies have shown that distinct bacterial products activate cells via different TLR proteins and that different TLR agonists can elicit different patterns of cytokine production. Unlike cellular responses to Gram-negative bacteria, TLR-dependent activation of cells by Mycobacterium tuberculosis does not require CD14. Live M. tuberculosis bacilli can activate macrophages in vitro via either TLR2 or TLR4. Mycobacterial ligands responsible for cellular activation by distinct TLR-dependent pathways have been identified, but have not been biochemically characterized. The long-term objectives of this project are to characterize TLR-dependent signaling, and to define the roles that these signals play in eliciting innate immune responses in macrophages. The aims of this proposal are to (1) determine whether engagement of different TLR proteins activates both shared and distinct signal transduction pathways, (2) determine if engagement of different TLR proteins activates distinct functional response in macrophages, and (3) determine whether selective loss of TLR function results in altered innate immunity.