Date Published: July 22, 2019
Publisher: Public Library of Science
Author(s): Abdulhadi Suwandi, Alibek Galeev, René Riedel, Samriti Sharma, Katrin Seeger, Torsten Sterzenbach, Lucía García Pastor, Erin C. Boyle, Ohad Gal-Mor, Michael Hensel, Josep Casadesús, John F. Baines, Guntram A. Grassl, Andreas J. Baumler.
Expression of ABO and Lewis histo-blood group antigens by the gastrointestinal epithelium is governed by an α-1,2-fucosyltransferase enzyme encoded by the Fut2 gene. Alterations in mucin glycosylation have been associated with susceptibility to various bacterial and viral infections. Salmonella enterica serovar Typhimurium is a food-borne pathogen and a major cause of gastroenteritis. In order to determine the role of Fut2-dependent glycans in Salmonella-triggered intestinal inflammation, Fut2+/+ and Fut2-/- mice were orally infected with S. Typhimurium and bacterial colonization and intestinal inflammation were analyzed. Bacterial load in the intestine of Fut2-/- mice was significantly lower compared to Fut2+/+ mice. Analysis of histopathological changes revealed significantly lower levels of intestinal inflammation in Fut2-/- mice compared to Fut2+/+ mice and measurement of lipocalin-2 level in feces corroborated histopathological findings. Salmonella express fimbriae that assist in adherence of bacteria to host cells thereby facilitating their invasion. The std fimbrial operon of S. Typhimurium encodes the π-class Std fimbriae which bind terminal α(1,2)-fucose residues. An isogenic mutant of S. Typhimurium lacking Std fimbriae colonized Fut2+/+ and Fut2-/- mice to similar levels and resulted in similar intestinal inflammation. In vitro adhesion assays revealed that bacteria possessing Std fimbriae adhered significantly more to fucosylated cell lines or primary epithelial cells in comparison to cells lacking α(1,2)-fucose. Overall, these results indicate that Salmonella-triggered intestinal inflammation and colonization are dependent on Std-fucose interaction.
Glycosylation is an important type of post-translational modification of proteins and lipids and is involved in the regulation of a wide range of processes at the cellular and molecular level. The gastrointestinal tract is home to a vast array of glycan structures and glycoconjugates , where the mucosal surface is the site of complex interactions between the intestinal microbiota, intestinal barrier, and immune system. The mucosal surface is characterized by a heavily glycosylated mucus layer produced by goblet cells as well as membrane-bound glycosylated proteins and lipids that form them . These glycoconjugates can be utilized by intestinal commensal bacteria and pathogens as molecular attachment sites or as nutrients . Importantly, host-derived glycans can help foster beneficial relationships with symbiotic microbes, such as Bacteroides thetaiotaomicron, by providing an energy source in the absence of dietary polysaccharides .
Variation in human glycosylation influences various metabolic diseases, cancers, inflammatory diseases, and susceptibility to infectious pathogens. Genome-wide association studies show that FUT2 nonsense polymorphisms are associated with increased risk for Crohn’s disease  and primary sclerosing cholangitis . Genetic variation in FUT2 is also linked to susceptibility to infections with bacterial and viral pathogens including Helicobacter pylori , norovirus [26, 27], Enterotoxigenic E. coli , and progression of HIV . In this study, we investigated the role of Fut2 expression for S. Typhimurium infection and found that Std fimbriae-fucose interaction was important for Salmonella-induced inflammation and colonization.