SugarBlock · Unraveling the protein glycosylation of Plasmodium falciparum is crucial for development of novel therapeutics against malaria
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-08-29 → 2018-08-28
- EU contribution
- €158,122
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Unraveling the protein glycosylation of Plasmodium falciparum is crucial for development of novel therapeutics against malaria
The project aims to increase our limited understanding of protein glycosylation patterns in the Plasmodium spp. parasites, the causative agent of malaria. Glycosylation modifies protein by enzymatically adding glycans during protein synthesis. It plays crucial biological roles such as cellular recognition, signal transduction, modulation of immune response and host-pathogen interactions. The common types include N-linked, O-linked and GPI-anchor protein glycosylation and the less studied C-mannosylation, O-fucosylation and O-GlcNAcylation. Currently our knowledge of their expression patterns in the parasites remains incomplete. O-fucosylation was recently identified on 2 major Plasmodium proteins, CSP and TRAP, which are common targets in malaria vaccine development. The design of the only approved malaria vaccine, RTS,S, is partially based on the specific domains of CSP, which are amenable to protein glycosylation. Its implication in vaccine design remains to be determined. Another key recent advance showed that unknown α-galactose (α-gal)-containing proteins in Plasmodium sporozoites induced the production of antibodies which were able to provide complete protection in malaria-infected mice. Such level of protection is not achieved with the current vaccine, but much remains unclear about the molecular characteristics of these glycosylated proteins in various parasite forms found in the different stages of the complex life cycle of the parasites. These include sporozoites and merozoites and the various blood-stage parasitic forms (rings, trophozoites, schizonts) and gametocytes. In this project, we studied protein glycosylation of sporozoites, merozoites and blood-stage parasites, with a focus on α-gal containing proteins in Plasmodium falciparum (Pf), the most virulent form of human malaria, and Plasmodium berghei (Pb), the rodent form which serves as a good model to study human malaria. We also investigated the proteins found in the salivary glands of Pf-infected and non-infected mosquitoes.
Data: CORDIS, © European Union
Project objective
Annually, malaria causes 200 million clinical cases and more than half a million deaths. Works carried out more than 40 years ago demonstrated that a malaria vaccine offering sterile protective immunity in humans was possible, but the efforts to develop a modern, recombinant ‘subunit’ malaria vaccine only confer short term protection against clinical malaria in 35-50% of recipients. Several evidences support the presence of foreign short N-glycans and other minor glycosylations in the surfaces of the parasite, Plasmodium faciparum, the causative agent of malaria. In addition, recent studies show that Plasmodium sporozoites present also unknown α-galactose containing antigens in their surface and that antibodies against them provide sterile protection against malaria in mice. We propose to completely characterize the protein glycosylation present in the surface of the extracellular sporozoites, that travel from the mosquito to the liver, and merozoites, that invade human erythrocytes. We will use different quasi-targeted glycoproteomic approaches, based on the expected simplicity and low variability of these glycosylations in the parasite surface and their affinity to well characterized lectins. The investigation of these uncommon parasitic glycosylations may expose an unexpected Achilles’ heel in the Plasmodium parasite that could be exploited to halt sporozoite development and/or stop merozoite invasion and induce protection against malaria, mimicking what has already been achieved using carbohydrate-protein conjugate vaccines against bacterial infections.
Original text from CORDIS.
Participants
- FUNDACION PRIVADA INSTITUTO DE SALUD GLOBAL BARCELONA · BarcelonaCoordinatorSpain
Links
Data: CORDIS, © European Union