Microbial Modulation of Physiology and Behavior of C. elegans

项目摘要 自2007年以来一直得到NIGMS支持的我们研究计划的长期目标是 了解宿主-微生物相互作用如何影响秀丽隐杆线虫的生理和行为， 预期对简单动物宿主的研究将提供对 微生物和更复杂的动物宿主。我们带来了广泛的跨学科视角， 基于C.从优雅的到跨越的研究 先天免疫是一种进化上保守的途径，是连接感染和 免疫与细胞和有机体对压力的反应，以及与微生物的相互作用如何影响 神经元信号和行为的C.优雅我们最近的焦点，和这个项目的主要目标， 在接下来的五年里，是了解细菌如何影响神经系统信号和C。 优雅我们已经描述了特定的毒性相关的次级代谢产物是如何产生的， 病原性细菌铜绿假单胞菌可以调节TGF-β配体在一对 C.感觉神经元elegans促进回避行为，定义了遗传，神经元和化学基础 微生物代谢物调节宿主生物行为的分子机制。我们有 进一步确定了环境和内源性线索如何汇聚在神经内分泌调节上， 基因表达，揭示了控制决策的输入的层次调节 C的行为。优雅在确定了涉及P. 铜绿假单胞菌的感觉神经系统，我们将继续采取系统的遗传方法，把我们的 注意感染和内部状态的改变如何改变神经内分泌基因的问题 表达和行为。我们还计划以更探索的方式扩大研究范围， 确定由宿主相互作用调节的其他遗传和神经通路， 病原菌，如铜绿假单胞菌，但也有细菌物种已确定在密切 与C.在自然环境中。我们希望基因和整体实验 简单C. elegans主机将使我们能够全面分析如何 微生物代谢物作用于神经系统以调节神经内分泌生理学和行为。的 微生物群及其代谢物越来越多地涉及体内平衡的各个方面， 宿主动物疾病的发病机理。我们期待我们的研究C。优雅的人会对 了解其他宿主生物体中的宿主-微生物相互作用。

Project Summary The long-term goals of our research program, which has been supported by NIGMS since 2007, has been to understand how host-microbe interactions influence the physiology and behavior of Caenorhabditis elegans, with the anticipation that studies of the simple animal host will provide insights into interactions between microbes and more complex animal hosts. We have brought a broad interdisciplinary perspective, with an experimental approach grounded in the molecular genetics of C. elegans, to studies that have spanned evolutionarily conserved pathways of innate immunity, the integrative physiology that connects infection and immunity with cellular and organismal responses to stress, and how interactions with microbes influence neuronal signaling and behavior of C. elegans. Our most recent focus, and the principal goal of this project over the next five years, is to understand how bacteria influence nervous system signaling and behavior of C. elegans. We have described how specific virulence-associated secondary metabolites produced by the pathogenic bacteria Pseudomonas aeruginosa can modulate expression of a TGF-beta ligand in a pair of sensory neurons of C. elegans to promote avoidance behavior, defining a genetic, neuronal, and chemical basis for the molecular mechanisms by which microbial metabolites can modulate host organism behavior. We have further determined how environmental and endogenous cues converge on the regulation of neuroendocrine gene expression, revealing insight into the hierarchical regulation of inputs that control decision-making behavior of C. elegans. Having defined the molecular pathways involved the innate recognition of P. aeruginosa by the sensory nervous system, we will continue to take a systematic genetic approach to turn our attention to the question of how infection and changes in internal state can modify neuroendocrine gene expression and behavior. We also plan to expand the scope of our studies in a more exploratory manner, to identify additional genetic and neuronal pathways that are modulated by host interactions with not only pathogenic bacteria such as P. aeruginosa, but also bacterial species that have been identified in close association with C. elegans in its natural environment. We expect that the genetic and overall experimental tractability of the simple C. elegans host will enable us to work towards a comprehensive analysis of how microbial metabolites act on the nervous system to modulate neuroendocrine physiology and behavior. The microbiota and its metabolites have been increasingly implicated in diverse aspects of homeostasis and the pathogenesis of disease in host animals. We anticipate our studies of C. elegans will have implications for the understanding of host-microbe interactions in other hosts organisms.