Abstract
Plasmodium falciparum malaria remains one of the world's foremost health problems, primarily in highly endemic regions such as Sub-Saharan Africa, where it is responsible for substantial morbidity, mortality and economic losses. Malaria is a significant cause of severe disease and death in pregnant women and newborns, with pathogenesis being associated with expression of a unique variant of the multidomain Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) called VAR2CSA. Here, we characterize the polymorphism of the DBL3X domain of VAR2CSA and identify regions under selective pressure among placental parasites from women living in endemic western Kenya. In addition to significant levels of polymorphism, our analysis reveals evidence for diversification through intra-segmental recombination and novel mutations that likely contributed to the high number of unique VAR2CSA sequence types identified in this study. Interestingly, we also identified a number of critical residues that may be implicated in immune evasion through switching (or toggling) to alternative amino acids, including an arginine residue within the predicted binding pocket in subdomain III, which was previously implicated in binding to placental CSA. Overall, these findings are important for understanding parasite diversity in pregnant women and will be useful for identifying epitopes and variants of DBL3X to be included in a vaccine against placental malaria.
Highlights
Malaria in pregnancy is a disease syndrome with devastating social and medical complications requiring multidimensional solutions
While haploid in the human host, recent work has demonstrated that some isolates of P.falciparum contain more than one copy of var2csa [24], which may provide a selective advantage during the course of infection in pregnant women [25]
Our results indicate that the multiplicity of infection (MOI) ranged between 1–4 unique genotypes (Table 2)
Summary
Malaria in pregnancy is a disease syndrome with devastating social and medical complications requiring multidimensional solutions. Malaria-induced morbidity and mortality is largely attributable to the cytoadherent nature of Plasmodium falciparum infected erythrocytes. This cytoadherence is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a parasite protein encoded by the highly polymorphic var gene family and expressed at the surface of the infected erythrocytes. Expression of a single member of the var gene family, var2csa, mediates binding to a form of chondroitin sulfate A (CSA) unique to the placenta [3,4,5,6,7]. Several studies have shown that, after multiple pregnancies, women in malaria endemic regions develop antibodies that inhibit infected erythrocyte binding to CSA [8,9,10], supporting the notion that a vaccine based on placentasequestering parasites could provide protection against PM
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