Abstract
Infection with Plasmodium falciparum during pregnancy is one of the major causes of malaria related morbidity and mortality in newborn and mothers. The complications of pregnancy-associated malaria result mainly from massive adhesion of Plasmodium falciparum-infected erythrocytes (IE) to chondroitin sulfate A (CSA) present in the placental intervillous blood spaces. Var2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is the predominant parasite ligand mediating CSA binding. However, experimental evidence suggests that other host receptors, such as hyaluronic acid (HA) and the neonatal Fc receptor, may also support placental binding. Here we used parasites in which var2csa was genetically disrupted to evaluate the contribution of these receptors to placental sequestration and to identify additional adhesion receptors that may be involved in pregnancy-associated malaria. By comparison to the wild-type parasites, the FCR3Δvar2csa mutants could not be selected for HA adhesion, indicating that var2csa is not only essential for IE cytoadhesion to the placental receptor CSA, but also to HA. However, further studies using different pure sources of HA revealed that the previously observed binding results from CSA contamination in the bovine vitreous humor HA preparation. To identify CSA-independent placental interactions, FCR3Δvar2csa mutant parasites were selected for adhesion to the human placental trophoblastic BeWo cell line. BeWo selected parasites revealed a multi-phenotypic adhesion population expressing multiple var genes. However, these parasites did not cytoadhere specifically to the syncytiotrophoblast lining of placental cryosections and were not recognized by sera from malaria-exposed women in a parity dependent manner, indicating that the surface molecules present on the surface of the BeWo selected population are not specifically expressed during the course of pregnancy-associated malaria. Taken together, these results demonstrate that the placental malaria associated phenotype can not be restored in FCR3Δvar2csa mutant parasites and highlight the key role of var2CSA in pregnancy malaria pathogenesis and for vaccine development.
Highlights
Plasmodium falciparum causes the most severe form of human malaria, with over two million deaths per year
The hyaluronic acid (HA)-selected infected erythrocytes (IE) adhesion phenotype was further examined on bovine HA (bHA), chondroitin sulfate A (CSA) and CD36 coated to plastic Petri dishes (Fig. 1B)
While wild type FCR3 IE selected on bHA (FCR3-HA) or with the CSA binding phenotype (FCR3-CSA) bound to bHA and in higher numbers to CSA, 1F1 FCR3Dvar2csa mutant clone IE selected on bHA (1F1-HA) maintained their CD36 binding phenotype and did not acquire any binding to CSA and bHA (Fig. 1B)
Summary
Plasmodium falciparum causes the most severe form of human malaria, with over two million deaths per year. Complications of pregnancy-associated malaria (PAM) result mainly from massive sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the placental intervillous blood spaces [3]. Placental sequestration impacts both mother and fetus, contributing to premature delivery, intrauterine growth retardation, stillbirth, maternal anaemia, and increased neonatal and maternal mortality [4]. Women develop protective antibody responses that block CSA binding and recognize geographically diverse placental isolates [5,6], suggesting that a vaccine against PAM is feasible. To design a vaccine to protect pregnant women and their fetuses, it is crucial to define the range of host receptors and parasite ligands involved in placental sequestration
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