Trpv1 nociceptor neurons modulate immune cells to regulate intestinal immunity in enteric infection

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PROJECT SUMMARY/ABSTRACT Nociceptor neurons are peripheral sensory neurons that densely innervate the gastrointestinal (GI) tract, detecting noxious/harmful stimuli to mediate protective neural reflexes including pain. The gut is also resident to a diverse population of innate and adaptive immune cells that maintain homeostasis and protect against invasion. However, the role of nociceptor neurons in regulating gut immunology, barrier protection, and host defense is not well understood. Preliminary data shows that chemogenetic activation of Trpv1+ subpopulation of nociceptors induces major changes in the immune cell profile in the cecum and colon, including T cells and macrophages. Trpv1+ nociceptors send signals to second order neurons in the spinal cord or brainstem, but also have the ability to release neuropeptides and other signaling molecules at their peripheral terminals. Furthermore, the gut receives nociceptor input from two anatomically separate sources, spinal dorsal root ganglia (DRG) neurons as well as vagal nodose ganglia (NG) neurons. My previous data has shown that a large proportion of both spinal and vagal afferents innervating the colon are Trpv1+, however, vagal and spinal subpopulations have unique transcriptomic patterns that reflect clustering of transmembrane receptors and channels that determine sensory modalities (e.g., pH, temperature, mechanical). In addition, our laboratory has previously shown vagal and spinal nociceptors to modulate immune cell function through peptide release in the lungs and small intestine, respectively. Therefore, this proposal will test the hypothesis that vagal and spinal Trpv1+ gut-innervating neurons differentially modulate innate and adaptive immune cells through release of peptides which impacts the ability of the host to fight enteric infections. I will investigate if spinal or vagal Trpv1+ neurons are involved in neuroimmune interactions in the gut using chemogenetics, flow cytometry, and functional characterization of immune cells (Aim1). Next, I will determine if Trpv1+ neurons signal to immune cells via peptides using knockout and antagonists of known mediators of neuroimmune communication (Aim 2). Finally, I will assess if Trpv1+ neuronal activation/inhibition impacts the ability of the host to fight enteric infections, specifically Citrobacter rodentium (Aim 3). The results from this proposal will elucidate the role of Trpv1 nociceptors in modulating immune cells at steady state and after enteric infection. This may provide new insight for therapeutic targets of visceral bacterial infections.