Genetic analysis of innate immunity using C. elegans

摘要 先天免疫系统是宿主抵御微生物感染的前线，但其快速和 不受控制的激活会引发具有有害影响的杀菌机制。越来越多的证据 表明后生动物神经系统对来自内部和外部的刺激做出反应 外部环境起着调节装置的作用，它不仅控制微生物的死亡途径 还包括细胞内环境平衡机制。然而，考虑到神经系统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可能通过哪些机制 感知病原体和/或益生菌相关分子模式(MAMP)并控制先天 豁免权。利用线虫秀丽线虫，我们最近证明了G蛋白偶联 受体(GPCR)信号在至少9个不同的神经元中控制免疫反应，表明细胞非 来自不同神经元的自主信号可能作用于非神经组织来调节先天免疫 在生物体水平上的反应。上述神经元中的GPCR信号控制微生物的杀戮 途径和保守的未折叠蛋白反应途径，可能是缓解 在免疫激活过程中对蛋白质折叠的需求增加。在这份提案中，我们将使用各种 探索神经系统调节免疫这一普遍假设的分子和遗传技术 在整个动物水平上，宿主对病原体感染的反应过程中的动态平衡。

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.