This project addresses the mechanisms of the gut-brain axis by which animals interact with bacterial pathogens and their microbiota. The focus is on mechanisms by which the nervous system detects the presence of distinct microbes, and communicates with the intestinal epithelium to elicit host defense responses. Also of interest is how the intestinal epithelium communicates back with the nervous system to modulate host physiology and behavior. Over the past ten years, our research program has used C. elegans as a whole-animal, in vivo model. The advantages of C. elegans include its relative anatomical simplicity and conserved signaling mechanisms, which enable sophisticated in vivo approaches to dissect inter-organ communication during infection. In this period, we have made fundamental discoveries including the outsized roles of TFEB-related transcription factors, acetylcholine-WNT brain-gut signaling, and pathogen-induced neurodegeneration (PaIN), all of which are conserved in mammals. Thus, our prior research has contributed to the fundamental understanding of host-microbe interactions and opened new avenues of research. The present project builds on our prior success and on our new insights into the involvement of sensory neurons and neurodegeneration in the host-microbe interaction. The goals for the next five years are to elucidate the neuronal mechanisms of microbial sensing in complex environments, understand the mechanisms of PaIN, and elucidate the mechanisms of regulation of intestinal host defense genes via TFEB-related transcription factors by the nervous system, in vivo. Longer term, the overall vision is to produce a comprehensive understanding of organismal, cellular, and molecular events that take place during initiation and resolution of infection by pathogens and pathobionts in C. elegans, and to capitalize on the present and future success of this project by continuing to translate our fundamental findings to murine and human model systems of infection and inflammation. Because of its focus on the gut-brain axis and the evolutionary conservation of the mechanisms that we have uncovered, the project is relevant to a broad range of human diseases and conditions, including infections, immune-mediated diseases, neurodegenerative diseases, metabolic syndrome, and cancer. We anticipate that the knowledge gained from the proposed work will advance the field and be generally applicable to higher organisms, and thus inform the search for better therapeutics and diagnostics for human infections and inflammation.

R35GM149284

2023-06-01

2028-05-31