Roles of Toll Like Receptors in Innate Immunity

描述（由申请人提供）：最近发现的 果蝇Toll受体蛋白引起了人们对确定其作用的兴趣， 这些蛋白质在先天免疫中的作用。相关的果蝇蛋白质Toll和 18-惠勒是抗真菌和抗细菌反应所必需的， 飞翔紧紧人类基因组编码至少10种不同的Toll样受体（TLR） 蛋白质基因，尽管它们在体内的功能在很大程度上是未知的。已经 提出，巨噬细胞可能利用TLR蛋白作为其功能的一部分， 对细菌病原体的反应。在小鼠中，单个TLR中的突变 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，缺乏功能性TLR4的小鼠， 与正常小鼠相比，易受致命的分枝杆菌感染。我们 最近的特点是TLR依赖的激活巨噬细胞的整体 分枝杆菌和几种纯化的细菌细胞壁组分。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 不同的TLR激动剂可以引起不同的模式， 细胞因子产生。与革兰氏阴性菌的细胞反应不同， 结核分枝杆菌对细胞的TLR依赖性激活 需要CD14。利夫湾结核杆菌在体外可激活巨噬细胞 通过TLR2或TLR4。分枝杆菌配体负责细胞 已经鉴定了不同TLR依赖性途径的激活，但 没有被生物化学表征。本项目的长期目标 是表征TLR依赖性信号传导，并定义这些信号传导的作用。 信号在引发巨噬细胞中的先天免疫应答中起作用。的目的 该建议是（1）确定不同TLR蛋白的参与是否 激活共享和不同的信号转导途径，（2）确定 如果不同TLR蛋白的参与激活不同的功能反应， 在巨噬细胞中，和（3）确定TLR功能的选择性丧失是否 导致先天免疫力改变

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.