The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

Abstract

ABSTRACTSalmonella entericaserovar Typhimurium is a model organism used to explore the virulence strategies underlyingSalmonellapathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection againstSalmonellais still unclear. The intestinal mucus layer is composed primarily of the Muc2 mucin, a heavily O-glycosylated glycoprotein. The core 3-derived O-glycans of Muc2 are synthesized by core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2 but display a thinner intestinal mucus barrier. We began our investigations by comparingSalmonella-induced colitis and mucus dynamics inMuc2-deficient (Muc2−/−) mice,C3GnT−/−mice, and wild-type C57BL/6 (WT) mice.Salmonellainfection led to increases in luminal Muc2 secretion in WT andC3GnT−/−mice. WhenMuc2−/−mice were infected withSalmonella, they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and developing significantly higher barrier disruption and higher mortality rates, than WT mice. We found that the exaggerated barrier disruption in infectedMuc2−/−mice wasinvAdependent. We also tested the susceptibility ofC3GnT−/−mice and found that they carried pathogen burdens similar to those of WT mice but developed exaggerated barrier disruption. Moreover, we found thatMuc2−/−mice were impaired in intestinal alkaline phosphatase (IAP) expression and lipopolysaccharide (LPS) detoxification activity in their ceca, potentially explaining their high mortality rates during infection. Our data suggest that the intestinal mucus layer (Muc2) and core 3 O-glycosylation play critical roles in controllingSalmonellaintestinal burdens and intestinal epithelial barrier function, respectively.