title: The mucin Muc2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar Typhimurium colitis.
abstract: Salmonella enterica serovar Typhimurium is a model organism used to explore the virulence strategies underlying Salmonella pathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection against Salmonella is 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 comparing Salmonella-induced colitis and mucus dynamics in Muc2-deficient (Muc2(-/-)) mice, C3GnT(-/-) mice, and wild-type C57BL/6 (WT) mice. Salmonella infection led to increases in luminal Muc2 secretion in WT and C3GnT(-/-) mice. When Muc2(-/-) mice were infected with Salmonella, 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 infected Muc2(-/-) mice was invA dependent. We also tested the susceptibility of C3GnT(-/-) mice and found that they carried pathogen burdens similar to those of WT mice but developed exaggerated barrier disruption. Moreover, we found that Muc2(-/-) 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 controlling Salmonella intestinal burdens and intestinal epithelial barrier function, respectively.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Zarepour
authors.forename: Kirandeep
authors.initials: K
authors.lastname: Bhullar
authors.forename: Marinieve
authors.initials: M
authors.lastname: Montero
authors.forename: Caixia
authors.initials: C
authors.lastname: Ma
authors.forename: Tina
authors.initials: T
authors.lastname: Huang
authors.forename: Anna
authors.initials: A
authors.lastname: Velcich
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
mesh_terms: D000818:Animals; D003092:Colitis / Q000382:microbiology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism*; D011134:Polysaccharides; D012481:Salmonella Infections, Animal / Q000382:microbiology* / Q000473:pathology; D012486:Salmonella typhimurium / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; C524626:Muc2 protein, mouse; D055262:Mucin-2; D011134:Polysaccharides