CYTOADHERENCE IN MATERNAL MALARIA

Pennsylvania State Univ Hershey Med Ctr, Hershey PA

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Abstract

DESCRIPTION (provided by the applicant): In pregnant women, red blood cells infected with Plasmodium falciparum (IRBCs) selectively adhere in the placenta, causing several clinical manifestations including low birth weight, stillbirth, abortion of the fetus, and anemia and death in the mother. A number of studies have shown that placental IRBC adherence is mediated by chondroitin 4-sulfate (C4S). During the previous grant period, it was established that a uniquely low sulfated chondroitin sulfate proteoglycan (CSPG) is the natural placental receptor for IRBC adherence and several critical structural elements of C4S involved in the process were determined. In contrast to the level of information available on the C4S structural elements involved in IRBC adhesion, very little is known about the parasite adhesive protein on the IRBC surface that binds C4S. Another aspect of the placental IRBC adherence that is not fully understood is the possible role of additional receptors. Recently, hyaluronic acid and fetal Fc receptor have been implicated but their roles have not been studied. The long-term objective of this investigation is to delineate the structural interactions involved in the placental IRBC adherence, and use this knowledge to develop therapeutics and/or a vaccine for placental malaria. To accomplish this goal, the parasite adhesive protein has to be unequivocally identified and its adhesive domain determined. Therefore, the aims of this proposal are to investigate three important aspects that represent logical extensions of the studies during the previous granting period: (1) Determine fully the C4S structural elements involved in IRBC adhesion. Based on this information, develop tools for the identification of parasite adhesive protein. (2) Determine whether hyaluronic acid and fetal Fc receptor also mediate placental IRBC adhesion by testing blood samples from a large number of P. falciparum-infected placentas. (3) Identify and characterize the parasite adhesive protein that interacts with the placental CSPG by biochemical and functional genomic approaches, and then identify the protein domain that interacts with C4S by expression in yeast and functional analyses.