Studies of Caenorhabditis elegans innate immunity

描述（由申请人提供）：本提案描述了旨在鉴定和表征秀丽隐杆线虫先天免疫信号传导途径的实验。在过去的几年里，我的实验室率先开发了C。线虫的致病性模型是基于观察到大量的人类致病细菌和酵母杀死线虫。优雅这些病原体中的每一种都通过简单地替换C.线虫的正常食物来源（大肠杆菌菌株OP 50的菌苔）与病原体，并随时间监测线虫的存活。这种简单的基于摄食的致病性模型，加上强大的遗传和基因组技术，包括RNAi摄食文库，使C。elegans是一个有吸引力的模型，在其中剖析免疫反应信号通路。我们已经确定C.线虫对病原体攻击的应答涉及保守的p38 MARK信号传导途径、含有Toll-白细胞介素1受体（TIR）结构域的信号传导组分、程序性细胞死亡和抗微生物效应蛋白，所有这些也在哺乳动物先天免疫中起作用。使用正向和反向遗传方法，我们已经确定了至少六个C。线虫基因（tir-1、nsy-1、sek-1、mek-1、vhp-1和peptide-1），其在MARK先天免疫信号传导途径中起作用，所述MARK先天免疫信号传导途径与在哺乳动物先天免疫应答中起作用的p38 MARK信号传导途径同源。我们还表明，β 2胰岛素样信号通路在先天免疫信号传导中发挥作用。在初步的数据中，我们已经鉴定了各种新的基因，它们似乎编码C。线虫PMK-1（p38）信号通路以及其他免疫通路的组分。我们还证明了对病原体介导的杀伤的抗性可以独立于总体蠕虫寿命。本研究旨在进一步阐明PMK-1（p38）信号通路及其他信号通路在C. elegans免疫应答，并描绘长寿和病原体抗性之间的关系。

DESCRIPTION (provided by applicant): This proposal describes experiments designed to identify and characterize Caenorhabditis elegans innate immune signaling pathways. During the past several years, my laboratory has pioneered the development of C. elegans pathogenicity models based on the observation that a remarkably large number of human pathogenic bacteria and yeasts kill C. elegans. Each of these pathogens has been studied by simply replacing C. elegans' normal food source (a lawn of Escherichia coli strain OP50) with a pathogen, and monitoring the survival of the nematodes overtime. This simple feeding-based pathogenicity model coupled with powerful genetic and genomic technologies, including RNAi feeding libraries, makes C. elegans an attractive model in which to dissect immune response signaling pathways. We have established that the C. elegans response to pathogen attack involves a conserved p38 MARK signaling pathway, a Toll-lnterleukin 1 Receptor (TIR)-domain-containing signaling component, programmed cell death, and antimicrobial effector proteins, all of which also function in mammalian innate immunity. Using both forward and reverse genetic approaches, we have identified at least six C. elegans genes (tir-1, nsy-1, sek-1, mek-1, vhp-1 and pmk-1) that function in a MARK innate immune signaling pathway homologous to the p38 MARK signaling pathway that functions in the mammalian innate immune response. We have also shown that the DAF-2 insulin-like signaling pathway plays a role in innate immune signaling. In preliminary data we have identified a variety of new genes that appear to encode additional components of the C. elegans PMK-1 (p38) signaling pathway as well as components of other immune pathways. We have also demonstrated that resistance to pathogenmediated killing can be independent of overall worm longevity. The specific aims are designed to further elucidate the role of the PMK-1 (p38) signaling pathway and other signaling pathways in activating the C. elegans immune response and to delineate the relationship between longevity and pathogen resistance.