Developmental Stage- and Cell Cycle Number-Dependent Changes in Characteristics of Plasmodium falciparum -Infected Erythrocyte Adherence to Placental Chondroitin-4-Sulfate Proteoglycan

Abstract

The adherence of Plasmodium falciparum-infected red blood cells (IRBCs) in the human placenta is mediated by chondroitin-4-sulfate (C4S). Although IRBC binding to C4S has been unequivocally established, the adherence characteristics of IRBCs at different stages of parasite development and through successive parasite generations after selection for C4S adherence are not known. Here we show that IRBCs acquire a significant capacity to bind to C4S at as early as 14 h and exhibit maximum binding at 22 to 26 h postinvasion. Surprisingly, the IRBC binding ability decreases by approximately 50% at the late trophozoite and schizont stages. The binding strength of the IRBCs also gradually decreases during successive generations after selection for C4S binding, and at the 32nd generation, the binding capacity was only approximately 31% of that of IRBCs at the 2nd generation, suggesting that IRBCs eventually lose their C4S-adherent capacity. We also tested the susceptibility of the adhesive protein(s) on the IRBC surface to trypsin treatment at different stages of parasite development. The data show that IRBCs with late trophozoites are more resistant to trypsin treatment than those containing early trophozoites, indicating that parasite proteins expressed on the IRBC surface during trophozoite maturation partially mask accessibility of adhesive protein for binding to C4S. These data provide important insights into the expression pattern of the C4S-adhesive protein(s) on the IRBC surface, emphasizing the need for understanding the regulation of genes involved in IRBC binding to C4S. Our data also define the parasite stage at which IRBCs are suitable for studying structural interactions with C4S.