Absence of receptor guanylyl cyclase C enhances ileal damage and reduces cytokine and antimicrobial peptide production during oralSalmonellaTyphimurium infection

Abstract

AbstractNon-typhoidalSalmonelladisease contributes towards significant morbidity and mortality across the world. Host factors including IFN-γ, TNF-α and gut microbiota, significantly influence the outcome ofSalmonellapathogenesis. However, the entire repertoire of host protective mechanisms contributing toSalmonellapathogenicity 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 systemicSalmonellainfection burden. Survival following intra-peritoneal infection remained similar, indicating that GC-C offered protection via a gut-mediated response. Serum cortisol was higher inGucy2c-/-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 inGucy2c-/-mice, concomitant with a larger number of ileal tissue-associated bacteria. Transcription of key mediators inSalmonella-induced inflammation (IL-22/Reg3β) were altered inGucy2c-/-mice in comparison toGucy2c+/+mice. A reduction in fecal Lactobacilli, which are protective against Salmonella infection, was observed inGucy2c-/-mice.Gucy2c-/-mice cohoused with wild type mice continued to show reduced Lactobacilli and increased susceptibility to infection. Our study therefore suggests that receptor GC-C confers a survival advantage during gut-mediatedS. Typhimurium pathogenesis, presumably by regulatingSalmonella-effectormechanisms and maintaining a beneficial microbiome.