MINECO (Spanish Ministry of Economy)
Exploration of the singularities of the sugar nucleotide metabolism and description of novel glycosylation pathways in the malaria parasite
Programas de investigación: Malaria
We are progressively uncovering evidence pointing to the presence of short, non-complex glycosylations in Plasmodium parasites. Recent work reports that unknown a-galactose (a-gal) containing glycoconjugates on the surface of Plasmodium sporozoites induced antibody production providing sterile protection in malaria-infected mouse models. In addition, IgM antibodies against these a-gal antigens are associated with protection from P. falciparum infection in humans. In agreement, our work has revealed the unexpected presence in P. falciparum blood stages of a pool of UDP-galactose, which is the donor substrate of all galactosylation reactions, describing a probable biosynthetic pathway. Anti-a-gal based immunity is conferred in the pre-erythrocytic stages of parasite infection (i.e. prior to liver invasion) suggesting that malaria transmission could effectively be controlled at this important bottleneck of the parasite life cycle. Such level of sterile protection is not achieved with current vaccine development, making these a-gal-containing antigens an attractive therapeutic candidate for immunization.
Using as springboard our broad experience on the glycobiology of the malaria parasite, we propose to perform a complete characterization of the glycosylations found on the surface of extracellular forms of the parasite life cycle, focusing in Plasmodium sporozoites and merozoites. The aim of the proposed research is to use integrated glycomics, glycoproteomics and biochemical approaches aided by recent advances in analytical technologies, to verify the presence of Plasmodium glycoconjugates expressing specific immunogenic sugar epitopes. Furthermore, we aim to dissect the specificity of the anti-a-gal antibodies in individuals from endemic areas, as a tool to obtain valuable data about the immunodominant glycotopes responsible for eliciting anti-a-gal-associated protection against P. falciparum.
Altogether the investigation of these and other uncommon parasitic glycosylations may expose an unanticipated Achilles heel in the Plasmodium parasite that could be exploited to induce sterile protection against malaria, mimicking what has already been achieved using carbohydrate-protein conjugate vaccines against bacterial infections.