Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta

Plasmodium falciparum infection during pregnancy results in the accumulatio n of infected red blood cells (IRBCs) in the placenta, leading to poor preg nancy outcome. In the preceding paper (Achur, R.N., Valiyaveettil, M., Alkh alil, A., Ockenhouse, C. F., and Gowda, D.C. (2000) J. Biol. Chem. 275, 403 44-40356), we reported that unusually low sulfated chondroitin sulfate prot eoglycans (CSPGs) in the intervillous spaces of the placenta mediate the IR BC adherence. In this study, we report the structural requirements for the adherence and the minimum chondroitin 4-sulfate (C4S) structural motif that supports IRBC adherence. Partially sulfated C4Ss with varying sulfate cont ents were prepared by solvolytic desulfation of a fully sulfated C4S. These and other nonmodified C4Ss, with different proportions of 4-, 6-, and nons ulfated disaccharide repeats, were analyzed for inhibition of IRBC adherenc e to the placental CSPG. C4Ss containing 30-50% 4-sulfated and 50-70% nonsu lfated disaccharide repeats efficiently inhibited IRBC adherence; C6S had n o inhibitory activity. Oligosaccharides of varying sizes were prepared by t he partial depolymerization of C4Ss containing varying levels of 4-sulfatio n, and their ability to inhibit the IRBC adherence was studied. Oligosaccha rides with six or more disaccharide repeats inhibited IRBC adherence to the same level as that of the intact C4Ss, indicating that a dodecasaccharide is the minimum structural motif required for optimal IRBC adherence. Of the C4S dodecasaccharides, only those with two or three sulfate groups per mol ecule showed maximum IRBC inhibition. These data define the structural requ irements for the IRBC adherence to placental CSPGs with implications for th e development of therapeutics for maternal malaria.