RT Journal Article SR Electronic T1 Absence of receptor guanylyl cyclase C enhances ileal damage and reduces cytokine and antimicrobial peptide production during oral Salmonella Typhimurium infection JF bioRxiv FD Cold Spring Harbor Laboratory SP 214163 DO 10.1101/214163 A1 Shamik Majumdar A1 Vishwas Mishra A1 Somesh Nandi A1 Mudabir Abdullah A1 Anaxee Barman A1 Abinaya Raghavan A1 Dipankar Nandi A1 Sandhya S. Visweswariah YR 2018 UL http://biorxiv.org/content/early/2018/02/10/214163.abstract AB 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/Reg3β) were altered in Gucy2c-/- mice in comparison to Gucy2c+/+ mice. A reduction in fecal Lactobacilli, which are protective against Salmonella infection, was observed in Gucy2c-/- 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-mediated S. Typhimurium pathogenesis, presumably by regulating Salmonella-effector mechanisms and maintaining a beneficial microbiome.