Genetic analysis of innate immunity using C. elegans

描述（由申请人提供）：先天免疫系统在病原体识别时的激活导致对入侵微生物的快速和明确的杀微生物反应，该反应经过微调以防止反应中的有害缺陷或过量。越来越多的证据表明，免疫反应是由反射性操作的神经回路快速协调的。然而，鉴于哺乳动物神经系统和免疫系统的复杂性，这两个系统相互影响的确切机制仍未得到充分研究。本提案描述了旨在阐明神经系统调节先天免疫机制的实验。利用秀丽隐杆线虫，我们最近证明了先天免疫不仅在细胞自主水平上受到调节，而且还通过表达g蛋白偶联受体的神经元在细胞非自主水平上受到调节。更具体地说，我们发现NPR-1，一种类似于哺乳动物神经肽Y受体的GPCR，参与秀丽隐杆线虫中控制p38/PMK-1 MAPK通路的神经回路。我们实验室的其他研究表明，OCTR-1是神经系统中表达的章鱼胺的肾上腺素能GPCR，控制非神经元组织中表达的p38/PMK-1途径和未折叠的反应途径，这对于缓解免疫激活过程中对蛋白质折叠的需求增加是必要的。具体在本次提案中，我们将使用多种分子

DESCRIPTION (provided by applicant): Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is fine-tuned to prevent deleterious deficiencies or excesses in the response. Increasing evidence indicates that immune responses are rapidly coordinated by neural circuits that operate reflexively. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence each other remain understudied. This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that innate immunity is not only regulated at the cell autonomous level, but also at the cell non-autonomous level through neurons expressing G-protein-coupled receptors. More specifically, we found that NPR-1, a GPCR similar to mammalian neuropeptide Y receptors, participates in a neural circuit that controls the p38/PMK-1 MAPK pathway in C. elegans. Additional studies from our laboratory indicate that OCTR-1, which is an adrenergic GPCR for octopamine expressed in the nervous system, controls the p38/PMK-1 pathway and unfolded response pathways that are expressed in non-neuronal tissues and that are necessary to alleviate the increased demand on protein folding during immune activation. In this proposal specifically, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during host response to pathogen infections at the whole animal level. Given the conserved nature of innate immune responses and of GPCR-mediated signaling in the nervous system, the proposed studies should lead to a better understanding of some of the mechanisms by which the metazoan nervous and innate immune systems influence each other.