ROLES OF TOLL LIKE RECEPTORS IN INNATE IMMUNITY

最近发现的哺乳动物同源的果蝇Toll受体蛋白引起了兴趣，在确定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-惠勒是果蝇抗真菌和抗细菌反应所必需的。 人类基因组编码至少10种不同的Toll样受体（TLR）蛋白基因，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蛋白作为其对细菌病原体的应答的一部分。 在小鼠中，单个TLR基因的突变导致对革兰氏阴性细菌脂多糖（LPS）的反应性丧失，并增加对细菌感染的易感性。 我们和其他人，最近的特点是TLR依赖激活巨噬细胞的全细菌和几个纯化的细菌细胞壁成分。 这些研究表明，不同的细菌产物通过不同的TLR蛋白激活细胞，并需要CD 14，一种LPS受体，也结合各种细菌细胞壁成分。 与这些细菌不同，结核分枝杆菌的TLR依赖性细胞活化不需要CD 14。 已经鉴定了通过不同TLR依赖性途径负责细胞活化的分枝杆菌配体，但尚未进行生物化学表征。 该项目的长期目标是表征TLR依赖性信号传导，并确定这些信号在巨噬细胞中引发先天免疫应答中发挥的作用。 本提案的目的是（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）确定不同TLR蛋白的参与是否激活巨噬细胞中不同的功能反应，以及（3）确定TLR功能的选择性丧失是否导致先天免疫改变。

The recent discovery of mammalian 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 ani-fungal and anti-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 a loss of responsiveness to Gram-negative bacterial lipopolysaccharide (LPS), and increased susceptibility to bacterial infection. We, and others, have recently characterized the TLR-dependent activation of macrophages by whole bacteria and several purified bacterial cell wall components. These studies have shown that distinct bacterial products activate cells via different TLR proteins and require CD14, an LPS receptor that also binds a variety of bacterial cell wall components. Unlike these many bacteria, TLR-dependent activation of cells by Mycobacterium tuberculosis bacilli does not require CD14. 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 responses in macrophages, and (3) determine if selective loss of TLR function results in altered innate immunity.