Interaction of Shiga toxin with primary human intestinal and renal epithelial cells: glycovesicles as novel toxin inhibitors

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Shiga toxin (Stx) produced by EHEC causes life-threatening complications such as the hemolytic uremic syndrome (HUS), which are thought to be mainly attributed to Stx-mediated injury of endothelial cells of the kidney and the brain. We could recently show that besides endothelial cells human colonic and renal epithelial cell lines do express the Stx glycosphingolipid (GSL) receptors globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer) and are sensitive towards the clinically highly relevant Stx1a and Stx2a subtypes as well. Latest results indicate that still less investigated primary human epithelial cells of the colon and the kidney also exhibit Stx receptors. The aim of this project is to explore for both types of primary epithelial cells (1) which Gb3Cer- and Gb4Cer-lipoforms are expressed and whether the Stx-binding GSLs are associated with lipid rafts, (2) how the Stx-GSL-interaction proceeds in real time using lipid raft-analogous membranes derived from the epithelial cells, (3) how and to which extent Stx1a and Stx2a damage primary colon and kidney epithelial cells, and (4) whether the Stx-mediated cellular damage and the molecular interaction of Stx with the genuine GSL receptors can be competitively inhibited by using newly developed Stx-binding neoglycolipids, which will be applied inserted in vesicles as glycovesicles. The project could promote the development of novel options for prevention and therapy of EHEC-mediated infections.