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VAR2CSA binding phenotype has ancient origin and arose before Plasmodium falciparum crossed to humans: implications in placental malaria vaccine design
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Edité par CCSD ; Nature Publishing Group -
International audience. VAR2CSA is a leading candidate for developing a placental malaria (PM) vaccine that would protect pregnant women living in malaria endemic areas against placental infections and improve birth outcomes. Two VAR2CSA-based PM vaccines are currently under clinical trials, but it is still unclear if the use of a single VAR2CSA variant will be sufficient to induce a broad enough humoral response in humans to cross-react with genetically diverse parasite populations. Additional immuno-focusing vaccine strategies may therefore be required to identify functionally conserved antibody epitopes in VAR2CSA. We explored the possibility that conserved epitopes could exist between VAR2CSA from the chimpanzee parasite Plasmodium reichenowi and Plasmodium falciparum sequences. Making use of VAR2CSA recombinant proteins originating from both species, we showed that VAR2CSA from P. reichenowi (Pr-VAR2CSA) binds to the placental receptor CSA with high specificity and affinity. Antibodies raised against Pr-VAR2CSA were able to recognize native VAR2CSA from different P. falciparum genotypes and to inhibit the interaction between CSA and P. falciparum-infected erythrocytes expressing different VAR2CSA variants. Our work revealed the existence of crossspecies inhibitory epitopes in VAR2CSA and calls for pre-clinical studies assessing the efficacy of novel VAR2CSA-based cross-species boosting regimens. Placental malaria (PM) is a serious complication of malaria infection associated with accumulation of Plasmodium falciparum infected erythrocytes (IEs) in the placental intervillous space 1-3 , leading to adverse health consequences for both mother and child 4. Pregnant women living in malaria endemic areas gradually acquire antibodies that limit placental infections 5 , thus diminishing the severe clinical outcomes associated with PM. In contrast to parasite populations sequestering in the peripheral microvasculature, which bind to endothelial cell receptors such as CD36, intercellular adhesion molecule 1 (ICAM-1) and endothelial protein C receptor (EPCR) 6-8 , placental IEs bind to an unusually low-sulphated form of chondroitin sulphate A (CSA) found in the placental intervillous spaces 9,10. The placental binding tropism is mediated by a single P. falciparum variant antigen, VAR2CSA, which is expressed at the surface of placental IEs 11-14. VAR2CSA is an unusually strain-transcendent member of the highly polymorphic P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family, present in one or more gene copies in every P. falciparum genotype 15. VAR2CSA is a large multidomain protein consisting of six Duffy-binding like (DBL) domains (three DBLx, followed by three DBLε). It also contains a CIDR PAM domain between the DBL2x and DBL3x domains, in a region that is also referred to as interdomain 2 (ID2). The core CSA-binding site in VAR2CSA has been mapped to the DBL2x domain and the flanking interdomain 1 (ID1) and ID2 regions 16,17 .
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