Abstract
Malaria during pregnancy in Plasmodium falciparum endemic regions is a major cause of mortality and severe morbidity. VAR2CSA is the parasite ligand responsible for sequestration of Plasmodium falciparum infected erythrocytes to the receptor chondroitin sulfate A (CSA) in the placenta and is the leading candidate for a placental malaria vaccine. Antibodies induced in rats against the recombinant DBL4ε domain of VAR2CSA inhibit the binding of a number of laboratory and field parasite isolates to CSA. In this study, we used a DBL4ε peptide-array to identify epitopes targeted by DBL4ε-specific antibodies that inhibit CSA-binding of infected erythrocytes. We identified three regions of overlapping peptides which were highly antigenic. One peptide region distinguished itself particularly by showing a clear difference in the binding profile of highly parasite blocking IgG compared to the IgG with low capacity to inhibit parasite adhesion to CSA. This region was further characterized and together these results suggest that even though antibodies against the synthetic peptides which cover this region did not recognize native protein, the results using the mutant domain suggest that this linear epitope might be involved in the induction of inhibitory antibodies induced by the recombinant DBL4ε domain.
Highlights
Plasmodium falciparum induced malaria is a major cause of mortality and severe morbidity in large parts of the world, especially in sub-Saharan Africa
The disease is caused by sequestration of P. falciparum-infected erythrocytes (IE) in the placenta, mediated through the parasite ligand VAR2CSA, which binds to the placental receptor chondroitin sulfate A (CSA)
We have previously shown that antibodies induced against the VAR2CSA DBL4e-FCR3 protein can inhibit a broad panel of genotypically different fresh placental isolates [11]
Summary
Plasmodium falciparum induced malaria is a major cause of mortality and severe morbidity in large parts of the world, especially in sub-Saharan Africa. The disease is caused by sequestration of P. falciparum-infected erythrocytes (IE) in the placenta, mediated through the parasite ligand VAR2CSA, which binds to the placental receptor chondroitin sulfate A (CSA). Placental malaria (PM) is a major cause of maternal anemia, fetal growth retardation, stillbirth and delivery of low-birth-weight babies [3]. Women in high malaria transmission areas acquire antibodies against CSA-binding parasites as a function of parity, which explains why first-time pregnant women are most susceptible to malaria [4]. IgG acquired during pregnancy, recognize CSA-binding parasites of diverse geographical origin [9,10].
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