Glycoconjugates-Mediated Interactions in Malaria Pathogenesis

Adhesion of Plasmodium falciparum-infected red blood cells in the vital organs and multiplication of parasites to high density and induction of inflammatory cytokines in response to the parasite toxic factors are central to the development of severe malaria. Understanding the details of molecular and cellular interactions between the parasite and the host is important for the development of novel therapeutics and vaccine for malaria. Our laboratory is specifically interested in understanding the structures and interactions between P. falciparum and human glycoconjugates that lead to malaria pathogenesis.

Glycosylphosphatidylinositols of Plasmodium falciparum: Structure, cell signaling, structure-activity relationship and biosynthesis. Glycosylphosphatidylinositol (GPI) anchors of P. falciparum are believed to be responsible for cerebral and other severe malaria. Previously, we established that intraerythrocytic P. falciparum, unlike all other organisms, lack or has only very low levels of protein N- and O-glycosylation capacity and GPIs represent the major carbohydrate modification in the parasite proteins. Recently, we determined the structures of P. falciparum GPIs and showed that the parasite GPIs have distinct structural features and the purified GPIs can activate mammalian macrophages to stimulate the production of inflammatory cytokines. We have also studied structure-activity relationship in GPIs and the anti-GPI antibody responses in people in malaria endemic areas. These studies defined the structural requirements for GPI activity, revealed a novel outside-in activation mechanism for cell signaling by GPIs, and established age-dependent acquisition of anti-GPI antibodies by people in endemic areas. Studies currently in progress include investigating the role of anti-GPI antibodies in protection against severe malaria, understanding the structure-activity relationship, and GPI cell signaling mechanism.

In P. falciparum, several functionally important cell surface proteins (those involved in parasite invasion and survival) are GPI anchored. Since biosynthesis of GPIs is crucial for cell surface statement of these functional proteins, inhibition of GPI synthesis should prevent the propagation of parasites. In other studies, we have shown that GPI biosynthesis in P. falciparum is developmentally regulated and that inhibition of GPI biosynthesis is lethal to parasites. Currently, we are extending these studies to investigate novel inhibitors of parasite GPI biosynthesis.

Adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta. In pregnant women infected with P. falciparum, the infected red blood cells sequester in the placenta, causing severe health problems to the fetus and the mother (placental malaria). Our studies have revealed that the adherence of P. falciparum to the placenta is mediated by an extracellular chondroitin sulfate proteoglycan (CSPG) receptor in the intervillous spaces of the placenta. The CSPG has unusually low sulfated polysaccharide chains. The minimum CS chain structural motif required for adherence is a dodecasaccharide and optimal binding involves two sulfate groups per dodecasaccharide moiety.

In malaria endemic areas, primigravidas and to some extent secundigravidas are susceptible to placental malaria; multigravidas are relatively resistant. This is due to gravidity-dependent development falicparum adhesion- and phenotypic-specfic humoral and cellular immune responses. Recently, we have shown that the pattern of antibodies during pregnancy accounts for the gravidity dependent differential susceptibility to placental malaria. Currently, we are focusing on the identification of parasite proteins that bind placental CSPG. The goal is to study the details of molecular interactions between the parasite proteins and purified placental CSPG using biochemical, immunological and molecular biology approaches.