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095

THE ROLE OF PROTEIN GLYCOSYLATION IN THE VIRULENCE OF THE GASTRIC PATHOGENS HELICOBACTER PYLORI AND CAMPYLOBACTER JEJUNI

A Merkx-Jacques, C Creuzenet
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario

H. pylori and C. jejuni are Gram-negative gastro-intestinal pathogens whose virulence is highly affected by protein glycosylation. The former causes gastric ulcers and cancer, while the latter causes enteritis and neurological disorders. Due to emerging drug-resistant strains, new treatments are needed.
In both bacteria, the flagellins are essential virulence factors glycosylated by pseudaminic acid (PA). We have identified and disrupted genes required for PA synthesis in both bacteria, and shown that this affects flagellin production. Further analysis and glycoprotein staining revealed that in H. pylori, the PA pathway is necessary for the glycosylation of proteins other than flagellins and for the synthesis of additional virulence factors, including LPS and urease. Enzymatic deglycosylation analysis uncovered a second set of H. pylori proteins glycosylated with an unknown sugar synthesized by a PA-independent pathway. We have identified one as a membrane-associated isoform of an immunodominant antigen that protects H. pylori from oxidative stress.
Numerous C. jejuni glycoproteins also possess a heptasaccharide containing diacetamidobacillosamine (DAB). Our DAB biosynthesis mutant was deficient in at least one glycoprotein and was avirulent in a chicken model, underscoring the role of this pathway in virulence. We have shown that both PA and DAB pathways are present in C. jejuni cell extracts and are investigating through activity-based assays and glycoprotein blotting how different growth conditions related to pathogenesis affect the relative activities of both pathways.
Understanding how each pathway affects virulence will reveal the best targets for the development of glycosylation inhibitors to treat these major infections.

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