Genetic analysis of innate immunity using C. elegans

总结 先天性免疫系统是宿主防御微生物感染的前线，但其快速和有效的免疫系统是免疫系统的重要组成部分。 不受控制的活化会激发具有有害作用的杀微生物机制。越来越多的证据 表明后生动物的神经系统，它对来自内部和外部的刺激作出反应， 外部环境作为一种调节装置，不仅控制微生物的杀灭途径， 还包括细胞内稳态机制。然而，考虑到神经和免疫系统的复杂性， 在哺乳动物中，这两个系统相互影响的精确机制仍然没有得到充分的研究。 该提案描述了旨在阐明神经系统可能 感生病原体和/或益生菌微生物相关分子模式（MAMP），并控制先天性 免疫力利用线虫秀丽隐杆线虫，我们最近证明了G蛋白偶联 至少9种不同神经元中的GPCR信号控制免疫应答，表明细胞非GPCR信号在细胞内表达。 来自不同神经元的自主信号可以作用于非神经组织来调节先天免疫 生物体水平的反应。上述神经元中的GPCR信号传导控制微生物杀灭 途径和保守的未折叠蛋白反应途径，这可能是必要的，以减轻 免疫激活过程中对蛋白质折叠的需求增加。在本提案中，我们将使用各种 分子和遗传技术来探索神经系统调节免疫的一般假设， 在整个动物水平上，宿主对病原体感染的反应期间的内稳态。

SUMMARY The innate immune system is the front line of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence one another remain understudied. This proposal describes experiments designed to elucidate the mechanism by which the nervous system may sense pathogens and/or probiotic microbe-associated molecular patterns (MAMPs) and control innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that G-protein coupled receptor (GPCR) signaling in at least 9 different neurons controls immune responses, indicating that cell non- autonomous signals from different neurons may act on non-neural tissues to regulate innate immune responses at the organismal level. GPCR signaling in the aforementioned neurons controls microbial killing pathways and a conserved unfolded protein response pathway that may be necessary to alleviate the increased demand on protein folding during immune activation. In this proposal, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during the host response to pathogen infections at the whole animal level.