SabA Is the H. pylori Hemagglutinin and Is Polymorphic in Binding to Sialylated Glycans

Abstract

Adherence of Helicobacter pylori to inflamed gastric mucosa is dependent on the sialic acid–binding adhesin (SabA) and cognate sialylated/fucosylated glycans on the host cell surface. By in situ hybridization, H. pylori bacteria were observed in close association with erythrocytes in capillaries and post-capillary venules of the lamina propria of gastric mucosa in both infected humans and Rhesus monkeys. In vivo adherence of H. pylori to erythrocytes may require molecular mechanisms similar to the sialic acid–dependent in vitro agglutination of erythrocytes (i.e., sialic acid–dependent hemagglutination). In this context, the SabA adhesin was identified as the sialic acid–dependent hemagglutinin based on sialidase-sensitive hemagglutination, binding assays with sialylated glycoconjugates, and analysis of a series of isogenic sabA deletion mutants. The topographic presentation of binding sites for SabA on the erythrocyte membrane was mapped to gangliosides with extended core chains. However, receptor mapping revealed that the NeuAcα2–3Gal-disaccharide constitutes the minimal sialylated binding epitope required for SabA binding. Furthermore, clinical isolates demonstrated polymorphism in sialyl binding and complementation analysis of sabA mutants demonstrated that polymorphism in sialyl binding is an inherent property of the SabA protein itself. Gastric inflammation is associated with periodic changes in the composition of mucosal sialylation patterns. We suggest that dynamic adaptation in sialyl-binding properties during persistent infection specializes H. pylori both for individual variation in mucosal glycosylation and tropism for local areas of inflamed and/or dysplastic tissue. Helicobacter pylori infections are very common worldwide and cause chronic inflammation in the stomach (gastritis), which may progress to peptic ulcer disease and stomach cancer. In the gastric epithelium, H. pylori infections induce expression of inflammation-associated “sialylated” carbohydrates. The ability to bind to the glycosylated epithelial cells is considered to be essential for H. pylori to cause persistent infection and disease. Here the authors show that during established infection, H. pylori also binds to red blood cells in gastric mucosal blood vessels in both infected humans and Rhesus monkeys. The authors found that “sialic acid–binding adhesin” (SabA), is the bacterial surface protein that mediates binding of H. pylori to red blood cells. Furthermore, they show that clinical H. pylori isolates demonstrate “polymorphism” in their abilities to bind various sialylated carbohydrates, and that the variation in binding properties depends on the sialic acid–binding adhesin protein itself. This variability may adapt the binding properties of H. pylori both to individual hosts and the changing epithelial glycosylation patterns during chronic inflammation. Continuous adaptation to inflamed tissue during persistent infections is probably a general feature of microbial pathogens, although their binding properties have not yet been explored in detail.