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

描述（由申请人提供）：动物和植物的先天免疫系统已经进化为维持地方性微生物的健康“负荷”。“有益的”细胞在多细胞生物体的各个区室中增殖;这是先天免疫系统所能耐受的。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个信号被整合以产生适当水平的免疫原性应答。我们对病原体反应的分子和细胞协调的认识仍然存在很大的差距。线虫秀丽隐杆线虫是一种简单的，遗传学上易于处理的模式宿主，用于先天免疫的研究。最近的研究表明，C。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期间调节非典型未折叠蛋白应答（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介导的免疫应答。对于该提议，有三个具体目的：1）确定先天免疫应答期间CED-1活性的空间要求，2）分析调节先天免疫的神经回路，和3）表征调节CED-1依赖性abu基因表达的途径。本研究将鉴定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分子途径，细胞自主和非细胞自主，有助于对人类病原体的免疫和微生物肠道群落的耐受性。

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.