Microbial Modulation of Physiology and Behavior of C. elegans

项目摘要 我们的研究计划自2007年以来一直得到NIGMS的支持，其长期目标是 了解寄主-微生物相互作用如何影响秀丽线虫的生理和行为， 预计对简单动物宿主的研究将提供对相互作用的见解 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， 以线虫分子遗传学为基础的实验方法，已经跨越了 进化上保守的先天免疫途径，连接感染和 免疫与细胞和组织对压力的反应，以及与微生物的相互作用如何影响 线虫的神经元信号和行为。我们最新的关注点和这个项目的主要目标 接下来的五年，将了解细菌如何影响神经系统信号和C. 优雅女装。我们已经描述了特定的毒力相关次级代谢物是如何由 致病菌铜绿假单胞菌可以调节转化生长因子-β配体在一对 线虫感觉神经元促进回避行为，确定遗传、神经元和化学基础 微生物代谢物可以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信号在神经内分泌调节上的趋同 基因表达，揭示了控制决策的输入的分层规则 线虫的行为。已明确的分子途径涉及P。 铜绿假单胞菌受到感觉神经系统的影响，我们将继续采取系统的遗传方法来将我们的 关注感染和体内状态变化如何改变神经内分泌基因的问题 表情和行为。我们还计划以更具探索性的方式扩大研究范围，以 识别由宿主相互作用调节的其他遗传和神经元通路，不仅 致病细菌，如铜绿假单胞菌，以及近距离鉴定的细菌种类 在其自然环境中与线虫共生。我们预计基因和整体实验 简单线虫宿主的易操纵性将使我们能够致力于全面分析 微生物代谢产物作用于神经系统，调节神经内分泌生理和行为。这个 微生物区系及其代谢产物越来越多地涉及动态平衡的各个方面，以及 宿主动物疾病的发病机制。我们预计我们对线虫的研究将对 了解其他寄主生物体中的寄主-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.