Nociceptor Regulation of the Intestinal Immune Landscape During Salmonella Typhimurium Infection

Abstract

In response to an insult from an invading pathogen, the peripheral nervous system is a key part of the host’s immune response. While neuronal responses to inflammation are welldocumented, much less is known of the interactions between neurons and immune environment of the gut in direct response to pathogens. The gut is heavily innervated with nociceptive neurons, and we hypothesize that these nociceptive neurons have extensive crosstalk with microfold cells and the gut microbiome, particularly in response to infection by Salmonella typhimurium. To address these hypotheses, we have investigated both larger, systemic infectionbased phenotypes as well as cell-specific and microbiome-dependent phenotypes through both Salmonella typhimurium infection and loss-of-function mouse models. Cell-specific interactions that will be targeted for research will be between CGRP+ nociceptive neurons and microfold cells. Such neuronal loss-of-function models include RTX treated B6 mice, a toxin to systemically target CGRP+ nociceptive neurons for ablation, genetic knockouts for Nav1.8 nociceptive neurons, and pharmacological approaches, such as chronic opioid treatments. Experiments with microfold cells in treated mice have relied heavily on quantitative and qualitative analysis of immunohistochemistry with multiple markers. Infection-based phenotypes rely on colonization and dissemination through various tissues, including murine ileum, Peyer’s patches, cecum, mesenteric lymph nodes, spleen, and liver. Further analysis of gut microbiome composition uses 16s sequencing as well as RT-QPCR analyses. The goal is to understand how neurons integrate into host defense by regulating gut epithelial cells and the microbiome, both at homeostasis and during infection.