Abstract
Plasmodium falciparum infected erythrocytes (IE) accumulate in the placenta through the interaction between Duffy-binding like (DBL) domains of parasite-encoded ligand VAR2CSA and chondroitin sulphate-A (CSA) receptor. Polymorphisms in these domains, including DBL2X and DBL3X, may affect their antigenicity or CSA-binding affinity, eventually increasing parasitemia and its adverse effects on pregnancy outcomes. A total of 373 DBL2X and 328 DBL3X sequences were obtained from transcripts of 20 placental isolates infecting Mozambican women, resulting in 176 DBL2X and 191 DBL3X unique sequences at the protein level. Sequence alignments were divided in segments containing combinations of correlated polymorphisms and the association of segment sequences with placental parasite density was tested using Bonferroni corrected regression models, taking into consideration the weight of each sequence in the infection. Three DBL2X and three DBL3X segments contained signatures of high parasite density (P<0.003) that were highly prevalent in the parasite population (49–91%). Identified regions included a flexible loop that contributes to DBL3X-CSA interaction and two DBL3X motifs with evidence of positive natural selection. Limited antibody responses against signatures of high parasite density among malaria-exposed pregnant women could not explain the increased placental parasitemia. These results suggest that a higher binding efficiency to CSA rather than reduced antigenicity might provide a biological advantage to parasites with high parasite density signatures in VAR2CSA. Sequences contributing to high parasitemia may be critical for the functional characterization of VAR2CSA and the development of tools against placental malaria.
Highlights
Plasmodium falciparum binds carbohydrate molecules to recognize, attach and invade cells both in the human and mosquito hosts [1]
Development of interventions against malaria targeting P. falciparum cytoadhesion, such as vaccines or anti-adhesive adjuvant therapies, is hampered by our limited understanding of the effect that the extreme polymorphism of parasite ligands may have on host-parasite interactions
This study identifies 6 amino acid motifs in DBL2X and DBL3X domains of VAR2CSA -the ligand mediating P. falciparum infected erythrocytes (IE) adhesion to human receptor chondroitin sulphate-A (CSA)- that are predominantly transcribed by parasites causing placental infections of high parasite density
Summary
Plasmodium falciparum binds carbohydrate molecules to recognize, attach and invade cells both in the human and mosquito hosts [1]. Among the different parasite-encoded ligands involved in these interactions, those containing a specific fold structure called Duffybinding like (DBL) domain bind to host receptors such as glycophorin A, complement receptor 1 and chondroitin sulphate-A (CSA) to promote the invasion of erythrocytes by merozoites, the binding of infected erythrocytes (IE) to uninfected erythrocytes (‘rosettes’) and the sequestration of mature parasites in the placenta, respectively [2]. Recombinant DBL2X, DBL3X and DBL6e have shown to individually bind CSA [17,18,19,20], the precise molecular interaction is still not known in detail due to the absence of full-length VAR2CSA crystal structures. Recent studies suggest that residues providing the highest binding specificity lie within DBL2X domain [21], with contribution from DBL1X and DBL3X [22,23]
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