Role of CED-1 in the Systemic Response to Pathogen Infection in C. elegans

描述（由申请人提供）：动植物的先天免疫系统已经进化到维持一个健康的地方性微生物“负荷”。“有益的”共生体在多细胞生物的各个隔间中增殖；这是先天免疫系统所能容忍的。另一方面，先天免疫系统积极尝试（并且，大多数成功）抑制有害病原体的生长。来自宿主和微生物的多种信号被整合以产生适当水平的免疫原性反应。我们在病原体反应的分子和细胞协调方面的知识仍然存在很大差距。秀丽隐杆线虫是一种简单的，遗传上易于处理的模型宿主，用于研究先天免疫。最近的研究表明，秀丽隐杆线虫蛋白CED-1是哺乳动物清道夫受体的同源物，在宿主先天免疫应答过程中调节非规范未折叠蛋白反应（UPR）的激活。此外，已经证明神经系统通过g蛋白偶联受体（GPCR） OCTR-1控制ced -1介导的免疫反应。本研究有三个具体目标：1)确定先天免疫反应中CED-1活性的空间要求；2)分析调节先天免疫的神经回路；3)表征CED-1依赖性abu基因表达的调控途径。本研究将确定OCTR-1/CED-1上游和下游的先天免疫途径。这项工作将有助于表征细胞自主和非细胞自主的分子途径，这些途径有助于对人类病原体的免疫和肠道微生物群落的耐受性。

DESCRIPTION (provided by applicant): The innate immune system of animals and plants has evolved to maintain a healthy "load" of endemic microorganisms. "Beneficial" commensals proliferate in various compartments of multicellular organisms; this is tolerated by the innate immune system. On the other hand, the innate immune system actively attempts (and, mostly succeeds) to suppress growth of harmful pathogens. Multiple signals from both host and microbe are integrated to produce an appropriate level of immunogenic response. Large gaps in our knowledge of the molecular and cellular coordination of pathogen response remain. The nematode Caenorhabditis elegans is a simple, genetically-tractable model host for the study of innate immunity. Recent work has demonstrated that the C. elegans protein CED-1, a homologue of mammalian scavenger receptors, regulates activation of the non-canonical unfolded protein response (UPR) during the host innate immune response. Moreover, it has been demonstrated that the nervous system, via the G-protein coupled receptor (GPCR) OCTR-1, controls CED-1-mediated immune responses. For this proposal, there are three specific Aims: 1) determine the spatial requirement for CED-1 activity during an innate immune response, 2) analysis of neural circuits that regulate innate immunity, and 3) characterization of pathways that regulate CED-1-dependent abu gene expression. This study will identify innate immune pathways upstream and downstream of OCTR-1/CED-1. This work will help in characterizing molecular pathways, cell autonomous and non-cell autonomous, that contribute to immunity to human pathogens and tolerance of microbial gut communities.