Chagas disease and leishmaniasis are parasitic diseases caused by the protozoa Trypanosoma cruzi, and different Leishmania spp., respectively. Patients with T. cruzi or L. major infections have specific anti-α-Gal antibodies elicited by glycans with terminal non-reducing α-galactopyranosyl (α-Gal) residues commonly present in the various glycoconjugates of the parasites' glycocalyx. Since α-Gal is completely absent or masked in human glycoconjugates, it is highly immunogenic. Identifying the α-Gal-containing glycotopes that elicit anti-α-Gal antibodies opens doors for the discovery of specific diagnostic and prognostic biomarkers. The trypomastigote form of T. cruzi expresses glycosylphospatidylinositol (GPI) anchored mucin-like glycoproteins. Only one of the O-glycans, a linear trisaccharide, has been identified and fully characterized so far, but the majority of these glycans are branched, and their exact structures are still elusive. In addition to anti-α-Gal antibodies, Chagas disease patients also have antibodies that specifically target glycans with terminal nonreducing β-galactofuranosyl (β-Galf) residues. They are components of T. cruzi's major protein-free glycoinositolphospholipids (GIPLs) and are most likely also present in the parasite's GPI anchors. β-Galf is completely absent in humans, is highly immunogenic, and β-Galf-containing glycotopes may therefore be attractive biomarker candidates for Chagas disease. L. major expresses galactose-rich type-2 GIPLs which contain both, α-Gal and β-Galf. Based on known type-2 GIPL structures, small oligosaccharides have been identified as specific biomarkers for L. major infection, which are capable of the serological distinction from healthy individuals and individuals with an L. tropica infection. We have applied reversed immunoglycomics, a bottom-up approach that combines the synthesis of suspected glycotopes with serology, and identified specific glyco-biomarkers for T. cruzi, L. major, and recently also L. braziliensis infections. Our data show that the entire glycoconjugates or large oligosaccharides are not necessary as biomarkers, but that small terminal oligosaccharides can be sufficient to achieve high sensitivity and specificity in serological assays.

Discovery of carbohydrate-based biomarkers for protozoan parasitic infections

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ACS Fall 2022

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