Recent studies suggest that during malaria infection in pregnant women, the placenta selects for a subpopulation of Plasmodium falcifarum by chondroitin 4-sulfate (C4S)-binding. In malaria endemic areas, primigravid women develop maternal malaria and susceptibility to the disease deceases as the gravid status increases, suggesting that women develop a level of protective immunity over successive pregnancies. Determination of the structural motif of the placental C4S that interacts with the parasite infected red blood cells (PRBCs), understanding of details of receptor-ligand interactions, studies on the immune response to C4S- specific parasite ligand in multigravid women living in malaria endemic areas, and studies on the nature and structure of the parasite ligand are likely to assist the development of therapy/vaccine for maternal malaria. This proposal focuses on C4S-mediated adherence of PRBCs to human placenta chondroitin sulfate proteoglycans (CSPG). Our preliminary results suggest that either a specific structural motif within the C4S chains of placental CSPGs binds PRBCs or the PRBC adherence to placenta CSPG may involve secondary interactions by either core proteins of CSPGs/co-purifying proteins after the initial C4S-specific recognition. Preliminary studies also show that specific oligosaccharides inhibit PRBC adherence to placenta CSPG. The overall goals of this proposal are to: (1) Purify human placental CSPGs, and study the glycosaminoglycan structures and PRBC binding characteristics of the CSPGs. (2) Determine whether the core proteins of CSPGs/co-purifying proteins participate in PRBC binding. (3) Immunofluorescence localization of PRBC- binding CSPG(s) in placenta. (4) Elucidation of the minimum size and fine structural specificity of the C4S motif that supports PRBCs adherence. (5) Evaluation of C4S ligand-specific immune protection in multigravid women living in malaria endemic areas. The long term goals of this study are to: (a) understand why placenta specifically selects for C4S-binding P. falciparum; (b) study the expression of the PRBC-binding receptor in placenta; (c) characterize the C4S- binding ligand on PRBCs; (d) study C4S oligosaccharides or oligosaccharide-mimetics for maternal malaria therapy; (e) develop C4S oligosaccharide-based drugs for maternal malaria therapy.
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