Unusually low-sulfated chondroitin 4-sulfate of human placenta and its role in placental malaria

The residents in malaria endemic areas generally acquire protective immunity to malaria by their adulthood. Despite this previously acquired natural immunity, women are highly susceptible to malaria during pregnancy, especially in their first pregnancy. This is due to the sequestration of a phenotypically different Plasmodium falciparum in the placenta by the adherence of the infected red blood cells (IRBCs). Because, prior to first pregnancy, women were not exposed to the placental adherent parasite at significant levels, they lack the phenotype-specific immunity. Therefore, infection during pregnancy leads to placental malaria, which is associated with a number of clinical manifestations. The adherence of P. falciparum IRBCs in the placenta is mediated predominantly by an unusually low sulfated aggrecan family chondroitin sulfate proteoglycan localized in the intervillous space of the placenta. The IRBC binding requires the participation of both 4-sulfated and nonsulfated disaccharide repeats of the chondroitin sulfate chains. The minimal structural motif required for optimal binding is a dodecasaccharide with two 4-sulfated and four non-sulfated disaccharides. P. falciparum erythrocyte membrane protein 1, a product of the var gene family, expressed on the surface of IRBCs has been proposed as the ligand for the IRBC adherence. In this review, we summarize our current knowledge on the structure of the placental chondroitin sulfate proteoglycan receptor, the identity of the parasite ligand, and chondroitin sulfate structural requirements for IRBC adherence.