Glycan-Glycan Interaction Determines Shigella Tropism toward Human T Lymphocytes

Abstract

Direct interactions between bacterial and host glycans have been recently reported to be involved in the binding of pathogenic bacteria to host cells. In the case of Shigella, the Gram-negative enteroinvasive bacterium responsible for acute rectocolitis, such interactions contribute to bacterial adherence to epithelial cells. However, the role of glycans in the tropism of Shigella for immune cells whose glycosylation pattern varies depending on their activation state is unknown. We previously reported that Shigella targets activated, but not nonactivated, human CD4+ T lymphocytes. Here, we show that nonactivated CD4+ T lymphocytes can be turned into Shigella-targetable cells upon loading of their plasma membrane with sialylated glycosphingolipids (also termed gangliosides). The Shigella targeting profile of ganglioside-loaded nonactivated T cells is similar to that of activated T cells, with a predominance of injection of effectors from the type III secretion system (T3SS) not resulting in cell invasion. We demonstrate that gangliosides interact with the O-antigen polysaccharide moiety of lipopolysaccharide (LPS), the major bacterial surface antigen, thus promoting Shigella binding to CD4+ T cells. This binding step is critical for the subsequent injection of T3SS effectors, a step which we univocally demonstrate to be dependent on actin polymerization. Altogether, these findings highlight the critical role of glycan-glycan interactions in Shigella pathogenesis.

The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

“…Human and bovine milk contain LacCer as a major GSL component , indicating that milk‐derived LacCer is a putative trap and blocking pathogen binding in the intestines, and that milk‐derived LacCer protects the host from invading pathogens. Interactions between the sugar moieties of gangliosides and the polysaccharide moieties of Shigella LPS were found to facilitate binding of bacteria to human CD4 + T cells . Taken together, these observations suggest that specific carbohydrate‐carbohydrate interactions between sugar moieties of GSL and of pathogen‐associated molecular pattern (PAMP) may be related to various immune disorders.…”

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

“…Although the role of the lipid A, core, and O antigen moieties in these processes have been extensively studied, a comprehensive understanding of the interplay between LPS and pathogenesis will require further research. For instance, interactions of LPS with host proteins has been the focus of many studies, but recent research suggests that glycan-glycan interactions between bacteria and their hosts may be more relevant than previously realized [194][195][196]. The advent of new glycan arrays could facilitate the screening and discovery of novel LPS interactions and yield new insights into pathogenic processes [194,197,198].…”

The Role of Glycans in Bacterial Adhesion to Mucosal Surfaces: How Can Single-Molecule Techniques Advance Our Understanding?

“…A later study by O’Riordan et al showed that glycans from several bacterial pathogens are able to interact with the glycan chains of lactoferrin, a protein present in bovine milk, although in this case no indications on the affinity of these bonds are given [ 142 ]. Finally, the body of evidence documenting the importance of glycan-glycan interactions for bacterial adhesion was recently extended by a study on the adhesion of Shigella to human lymphocytes [ 143 ]. Whereas Day and co-workers revealed the importance of glycan-glycan interactions in mediating binding of Shigella to host epithelial cells [ 139 ], this resent study by Belotserkovsky and co-workers provides evidence that glycan-glycan interactions are critical for Shigella pathogenesis by driving selective interactions with immune cells [ 143 ].…”

“…Finally, the body of evidence documenting the importance of glycan-glycan interactions for bacterial adhesion was recently extended by a study on the adhesion of Shigella to human lymphocytes [ 143 ]. Whereas Day and co-workers revealed the importance of glycan-glycan interactions in mediating binding of Shigella to host epithelial cells [ 139 ], this resent study by Belotserkovsky and co-workers provides evidence that glycan-glycan interactions are critical for Shigella pathogenesis by driving selective interactions with immune cells [ 143 ]. More precisely, they show that sialylated glycosphingolipids interact with the polysaccharide moiety of LPS, the major bacterial surface antigen, thus promoting Shigella binding to T cells.…”