Trypanosoma cruzi - Derived Sugar Epitopes - Synthesis and Immunology

Abstract

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease. As of today no effective vaccine has been developed for it. Certain developmental stages of T.cruzi express cell surface oligosaccharides with terminal alpha-galactosyl and rhamnosyl residues, which are believed to be highly immunogenic in humans. The exact structures and sizes of these epitopes are still unknown. Our quest is to shine light on the chemical structures of immunogenic alpha-Gal and alpha-Rha containing mono-, di-, and trisaccharides that are conjugated to a keyhole limpet hemocyanin (KLH) carrier protein through a combination of chemical synthesis and immunological studies. The compounds synthesized were screened for their ability to be recognized by Chagasic antibodies in an enzyme-linked immunosorbent assay (ELISA). The best recognized sugar-KLH conjugates were used to immunize alpha-1,3 Gal T-KO mice, which do not express cell surface proteins with terminal alpha-galactosides, and are therefore a suitable model for humans. We have successfully synthesized and conjugated a library of nine saccharides with terminal alpha-galactosyl or rhamnosyl moieties, which elicit various levels of antibody production in mice. Upon challenge of the immunized mice with lethal doses of live T. cruzi, prolonged survival was observed when compared to the control group. The work presented here has implications for the development of a carbohydrate-based vaccine for Chagas disease