Receptor guanylyl cyclase C confers protection during oral Salmonella Typhimurium infection by attenuating ileal damage and enhancing cytokine and antimicrobial peptide production

Non-typhoidal Salmonella disease contributes towards significant morbidity and mortality across the world. Host factors including IFN-γ, TNF-α and gut microbiota significantly influence the outcome of Salmonella pathogenesis. However, the entire repertoire of host protective mechanisms contributing to Salmonella pathogenicity is not completely appreciated. Here, we have investigated the roles of receptor guanylyl cyclase C (GC-C) that is predominantly expressed in the intestine, and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C (Gucy2c -/- ) displayed accelerated mortality following infection via the oral route, in spite of possessing comparative systemic Salmonella infection burden. Survival following intra-peritoneal infection remained similar, indicating that GC-C offered protection via a gut-mediated response. Serum cortisol was higher in Gucy2c -/- mice, in comparison to wild type (Gucy2c +/+ ) mice, and an increase in infection-induced thymic atrophy, with loss in immature CD4+CD8+ double positive thymocytes, was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting and distortion of villus architecture, was seen in Gucy2c -/- mice, concomitant with a larger number of ileal tissue-associated bacteria. Transcription of key mediators in Salmonella-induced inflammation (IL-22/IL-23/Reg3β) were altered in Gucy2c -/- mice. Downregulation of expression of GC-C and its endogenous ligands, guanylin and uroguanylin following infection in Gucy2c +/+ mice was observed. In conclusion, our study suggests that receptor GC-C confers a survival advantage during gut-mediated S. Typhimurium pathogenesis, presumably by regulating Salmonella-effector mechanisms in a cGMP-dependent manner.