Carbohydrate-Dependent Defense Mechanisms Against Helicobacter pylori Infection

Motohiro      Kobayashi; Heeseob      Lee; Jun      Nakayama; Minoru      Fukuda

Abstract

Helicobacter pylori is a Gram-negative bacterium that infects over 50% of the worlds population. This organism causes various gastric diseases such as chronic gastritis, peptic ulcer, and gastric cancer. H. pylori possesses lipopolysaccharide, which shares structural similarity to Lewis blood group antigens in gastric mucosa. Such antigenic mimicry could result in immune tolerance against antigens of this pathogen. On the other hand, H. pylori colonize gastric mucosa by utilizing adhesins, which bind Lewis blood group antigenrelated carbohydrates expressed on gastric epithelial cells. In chronic gastritis, lymphocytes infiltrate the lamina propria, and such infiltration is facilitated by 6-sulfo sialyl Lewis X-capped O-glycans, peripheral lymph node addressin (PNAd), on high endothelial venule (HEV)-like vessels. The number of HEV-like vessels increases as chronic inflammation progresses. Furthermore, PNAd formed on HEVlike vessels disappear once H. pylori is eradicated. These results indicate that PNAd plays an important role in H. pylori-associated inflammation. H. pylori barely colonizes gland mucous cell-derived mucin where α1,4-GlcNAc-capped O-glycans exist. In vitro experiments show that α1,4-GlcNAc-capped O-glycans function as a natural antibiotic to inhibit H. pylori growth. We recently identified cholesterol α-glucosyltransferase (CHLαGcT) using an expression cloning strategy and showed that this enzyme is specifically inhibited by mucin-type O-glycans like those present in deeper portions of the gastric mucosa. These findings show that a battery of carbohydrates expressed in the stomach is closely associated with pathogenesis and also prevention of H. pylori-related diseases.

Keywords: Helicobacter pylori, lipopolysaccharide, Lewis blood group antigen, adhesin, 6-sulfo sialyl Lewis X-capped O-glycan, α1,4-GlcNAc-capped O-glycan, cholesteryl-α-D-glucopyranoside, cholesterol α-glucosyltransferase