Genetic analysis of innate immunity using C. elegans

描述（由申请人提供）：该提案描述了旨在阐明神经系统调节先天免疫以应对病原体感染的机制的实验。我们在秀丽隐杆线虫方面的研究已经鉴定出在感染不同病原体时表现出异常反应的突变体。对这些缺乏免疫反应的秀丽隐杆线虫突变体的分析阐明了多种相互作用和交叉的遗传途径在包括人类在内的物种中高度保守的免疫反应中所起的作用。我们实验室的最新研究表明，秀丽隐杆线虫的先天免疫是由表达NPR-1的神经元调控的，NPR-1是一种与哺乳动物神经肽Y受体相关的g蛋白偶联受体。我们的研究表明，一个涉及NPR-1的神经回路可以抑制先天免疫反应。免疫抑制功能需要一个由tax-2和tax-4以及可溶性鸟苷酸环化酶GCY-35编码的环状gmp门控离子通道。此外，我们发现表达npr-1和gcy-35的感觉神经元积极抑制非神经元组织的免疫反应。一项全基因组微阵列分析显示，由于npr-1突变导致神经功能改变的动物，其先天免疫应答标记基因富集，包括受保守的PMK-1/p38丝裂原激活的蛋白激酶信号通路调控的基因。这一建议将继续我们的研究，利用秀丽隐杆线虫模型来阐明神经系统在调节先天免疫对抗细菌病原体中的作用。我们假设g蛋白偶联受体（gpcr）可能参与从病原体或感染部位接收输入并整合它们以协调适当的先天免疫反应的神经回路。有三个具体目的：1)鉴定表达调节先天免疫的gpcr的神经元。2)解剖调节先天免疫的神经回路。3)神经免疫通讯信号的识别和表征。拟议的研究将作为了解神经和免疫系统通过双向信号进行交流的机制的路线图。鉴于神经通讯和先天免疫反应的保守性，我们期望我们的工作将有助于更好地理解后生动物神经系统和先天免疫系统相互影响的机制。公共卫生相关性：我们计划继续我们的研究，以阐明神经系统在对细菌病原体的先天免疫反应的调节中的作用。更好地了解神经-免疫交流可能会导致先天性免疫系统缺陷疾病的新治疗靶点。

Description (provided by applicant): This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity in response to pathogen infection. Our work in Caenorhabditis elegans has led to the identification of mutants that exhibit aberrant responses when infected with different pathogens. Analysis of these C. elegans mutants deficient in immune responses is clarifying the roles of a variety of interacting and intersecting genetic pathways involved in immune responses highly conserved across species, including humans. The latest studies from our laboratory indicate that innate immunity in C. elegans is regulated by neurons expressing NPR-1, which is a G-protein-coupled receptor related to mammalian neuropeptide Y receptors. Our studies have demonstrated that a neural circuit involving NPR-1 functions to suppress innate immune responses. The immune inhibitory function requires a cyclic GMP-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we showed that npr-1- and gcy-35-expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 showed enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. This proposal will continue our studies utilizing a C. elegans model to clarify the role of the nervous system in the regulation of innate immunity against bacterial pathogens. We hypothesize that G-protein coupled receptors (GPCRs) may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate innate immune responses. There are three specific aims: 1) Identification of neurons expressing GPCRs that regulate innate immunity. 2) Dissection of the neural circuit that regulates innate immunity. 3) Identification and characterization of signals involved in neural- immune communications. The proposed studies will serve as a roadmap to understand the mechanisms by which the nervous and immune systems communicate through bidirectional signals. Given the conserved nature of neural communications and innate immune responses, we expect our work will lead to a better understanding of the mechanisms by which the metazoan nervous and innate immune systems influence each other. PUBLIC HEALTH RELEVANCE: We plan to continue our studies to clarify the role of the nervous system in the regulation of innate immune responses against bacterial pathogens. A better understanding of the neural-immune communication could lead to new therapeutic targets for diseases involving a deficient innate immune system.