Genetic analysis of innate immunity using C. elegans

描述(由申请人提供)：病原体识别后激活天然免疫系统会对入侵的微生物产生快速和明确的杀菌反应，并进行微调，以防止反应中有害的不足或过度。越来越多的证据表明，免疫反应是由反射操作的神经回路快速协调的。然而，考虑到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。这项建议描述了旨在阐明神经系统调节先天免疫机制的实验。利用线虫秀丽线虫，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，参与控制线虫p38/PMK-1 MAPK通路的神经回路。我们实验室的进一步研究表明，OCTR-1是神经系统中表达的章鱼的肾上腺素能GPCR，它控制着p38/PMK-1通路和未折叠的反应通路，这些通路在非神经组织中表达，对于缓解免疫激活过程中对蛋白质折叠的增加需求是必要的。具体地说，在这个提案中，我们将使用各种分子 以及基因技术，以探索神经系统在整个动物水平上调节宿主对病原体感染的反应期间的免疫动态平衡这一普遍假设。鉴于神经系统中先天免疫反应和GPCR介导的信号的保守性，拟议的研究应该有助于更好地理解后生动物神经和先天免疫系统相互影响的一些机制。

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.