Nonimmune immunoglobulin binding and multiple adhesion characterize Plasmodium falciparum -infected erythrocytes of placental origin

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Abstract
The harmful effects of pregnancy-associated malaria (PAM) are engendered by the heavy sequestration of Plasmodium falciparum -parasitized RBCs in the placenta. It is well documented that this process is mediated by interactions of parasite-encoded variant surface antigens and placental receptors. A P. falciparum erythrocyte membrane protein 1 variant, VAR2CSA, and the placental receptor chondroitin sulfate A (CSA) are currently the focus of PAM research. A role for immunoglobulins (IgG and IgM) from normal human serum and hyaluronic acid as additional receptors in placental sequestration have also been suggested. We show here ( i ) that CSA and nonimmune IgG/IgM binding are linked phenotypes of in vitro -adapted parasites, ( ii ) that a VAR2CSA variant shown to bind CSA also harbors IgG- and IgM-binding domains (DBL2-X, DBL5-ε, and DBL6-ε), and ( iii ) that IgG and IgM binding and adhesion to multiple receptors (IgG/IgM/HA/CSA) rather than the exclusive binding to CSA is a characteristic of fresh Ugandan placental isolates. These findings are of importance for the understanding of the pathogenesis of placental malaria and have implications for the ongoing efforts to develop a global PAM vaccine.