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Synthesis of oligosaccharides of immunological importance in Cryptococcus neoformans


Cryptococcus neoformans is an opportunistic human pathogen causing a life-threatening form of meningitis in immunocompromised individuals, especially in AIDS patients. The capsular polysaccharide is this yeast¿s main virulence factor. It allows the yeast t o cross the hemato-encephalitis barrier and subsequently disseminate in the central nervous system. Some of the antibodies, specific for the major component of the capsule, a glucuronoxylomannan (GXM) polysaccharide, are protective against infection. Howev er, knowledge of the exact nature of the repeating units of GXM associated to the various serotypes of C. neoformans and a fortiori that of the corresponding "protective" epitopes is lacking. Using synthetic oligosaccharides made "in demand", our goal is t o fill these crucial gaps. Indeed "protective" carbohydrate epitopes may be used both as prognostic tools as well as key components in the development of an efficacious GXM-derived conjugate vaccine. Besides, the GXM structure necessary and/or sufficient f or crossing the blood brain barrier might be identified. The originality of our project is the key in-house interactive partnership between genetics and chemistry. Using state-of-the-art glycochemistry, focus will be on the development of highly reactive c onvergent synthetic strategies. A set of key versatile mono- and disaccharide building blocks, optimized for target diversity and whenever possible compatible with solid phase synthesis, will be designed. Their appropriate combination will next lead to the oligosaccharide targets, selected according to hypotheses derived from screening for the biological properties of a large panel of randomly mutated strains. The Marie Curie fellow will be in charge of the synthesis and biological evaluation of the targets , including the study of their binding to a panel of anti-GXM antibodies.

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