Small intestinal Goblet cells and Goblet cell associated antigen passages assist translocation of pathogenic bacteria

Abstract

Abstract The intestinal epithelium forms an essential physicochemical barrier that separates luminal bacteria from underlying immune cells of the intestinal mucosa. Appropriate exposure of the immune cells to luminal antigens is crucial to ensure intestinal homeostasis and to respond to enteric infections. We recently demonstrated a previously unappreciated role of small intestinal (SI) Goblet cells (GCs) in delivering luminal antigens across the epithelium by forming goblet-cell associated antigen passages (GAPs) in the steady state. How pathogenic bacteria affect the formation of SI GAPs and the ability of pathogens to use GAPs as a portal of entry is largely unexplored. Here we report that in conventionally housed mice, luminal exposure to invasive Salmonella typhimurium, but not mutant non-invasive S. typhimurium, results in inhibition of SI GAPs within minutes. Moreover, overriding the ability of GCs to sense the pathogen by deleting MyD88 in GCs or inhibiting EGFR activation downstream of MyD88 during S. typhimurium infection allowed GAP formation, suggesting that GC intrinsic sensing of an invasive pathogen to shut off GAPs is a host defense mechanism. Fluorescent wildtype S. typhimurium preferentially localized around and within GCs forming GAPs. Deletion of GCs prevented the translocation of wildtype S. typhimurium to the SI draining mesenteric lymph node following oral infection, indicating that S. typhimurium uses GCs as a portal of entry. These findings identify a role of GC sensing of an invasive pathogen in inhibiting antigen delivery to the immune system and in limiting the translocation of pathogenic bacteria.