ABSTRACT
Adult men and women living in areas of stable malaria transmission enjoy immunity that limits parasitemia and disease due to P. falciparum. However, women have an increased susceptibility to malaria during pregnancy, especially first pregnancies. This susceptibility has often been ascribed to pregnancy-related immunosuppression, but this would not adequately explain differences between first and later pregnancies. P. falciparum characteristically sequesters in the vascular beds of various organs, and cerebral malaria is believed to arise from the accumulation of parasites adhering to vascular endothelium in the brain. Similarly, maternal malaria is characterized by a heavy parasite burden in the placenta. Sequestration confers a survival advantage to the parasite: mature parasites remain immobilized, avoiding passage through the spleen where they may suffer immunological clearance. Unlike other falciparum isolates, placental parasites commonly bind to chondroitin sulfate A, a glycan expressed on the surface of the syncytiotrophoblast. Because this receptor may not be accessible for parasite adhesion in the nonpregnant host, women may not have substantial exposure to the chondroitin sulfate A-binding subpopulation until first pregnancy, rendering primigravidae naïve to infection. Over successive pregnancies, women develop specific anti-adhesion immunity that blocks parasite adhesion to CSA, such that multigravid women are infected less frequently and with lower parasite densities compared to primigravid women. The paradigm of parasite adhesion and anti-adhesion immunity explains the epidemiology of pregnancy malaria, and suggests new approaches for preventing or treating maternal malaria.
