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.