Coordination of mucosal immune response to enteric bacterial pathogens by nociceptive innervation

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Project Summary Host-microbial interactions are a critical determinant of health. The gastrointestinal tract provides several overlapping mechanisms that function together to prevent entry of pathogens into the body. These protective mechanisms are provided through the coordinated of intestinal epithelial cells and immune cells in the lamina propria. While the specialized sensory nociceptive neurons that detect noxious stimuli such as pathogens, or the resulting host tissue damage are known to control immune function in the skin and lung, the contribution of these neurons to intestinal mucosal immunity is not known. Building on our preliminary data, the overall goals of this project are to precisely determine the role of sensory nociceptive neurons in the neuro-immune communication that limits enteric bacterial infection. This will be achieved by selective ablation of sensory neurons, and experiments to determine the source of SP and the targeted cells (SA1). How an enteric bacterial pathogen induces nociceptive activation in vitro and in vivo (SA2). Mechanistic understanding of the immunological effect of sensory neurons during enteric infection will be attained. Specifically, how nociceptor ablation impinges on dendritic cell migration, chemokine production, and adhesion molecule expression will be determined (SA3). Together, these proposed studies will decipher the contribution of sensory afferent nociceptive neurons to mucosal host defense during enteric bacterial infection.