Blocking of the receptor‐mediated invasion of erythrocytes by Plasmodium knowlesi malaria with sulfated polysaccharides and glycosaminoglycans

Abstract

Invasion of human erythrocytes by Plasmodium knowlesi requires the Duffy blood group antigen. P. knowlesi merozoites synthesize a 135-kDa polypeptide which binds to the Duffy antigen with receptor-like specificity. In this study, we show that the sulfated polysaccharide fucoidan and the glycosaminoglycan dextran sulfate inhibit the binding of the 135-kDa polypeptide to human Duffy-positive and rhesus erythrocytes while the chondroitin sulfates do not. Fucoidan and dextran sulphate also blocked the in vitro invasion of human Duffy b and rhesus erythrocytes cells by P. knowlesi merozoites. These inhibitors were more effective at blocking the binding of the 135-kDa polypeptide to human Duffy b erythrocytes than to rhesus erythrocytes, which correlated with them having a greater inhibitory effect on invasion of merozoites into human than into rhesus erythrocytes.The blocking by these sulfated sugars is not related to charge density on the polysaccharides; fucoidan with a relatively low charge density blocks binding of the 135-kDa polypeptide at 4 pg/ml, while the highly negatively charged chondroitin sulfates do not block binding even at the concentration of 1 mg/ml. Furthermore, fucoidanSepharose bound and removed the 135-kDa polypeptide from parasite culture supernatants with a selectivity equal to that of the Duffy blood group antigen. The negatively charged sulfate groups on fucoidan and dextran sulfate and the conformation in which they are held possibly mimic similarly charged groups on the Duffy antigen which bind the 135-kDa P. knowlesi polypeptide.The asexual erythrocyte cycle of malaria begins with growth and proliferation of the intraerythrocytic parasite to individual merozoites which, on rupture of the erythrocyte, invade other erythrocytes. Growth and proliferation then begins again in the newly invaded erythrocyte. Invasion of erythrocytes involves recognition of specific ligands on erythrocytes by receptors on merozoites [l]. In the case of Plasmodium knowlesi, a monkey malaria that invades human erythrocytes, at least one of these ligands is the Duffy blood group antigen [2]. Human erythrocytes lacking the Duffy antigen are not invaded by P. knowlesi merozoites, and invasion can be blocked with anti-Duffy antibodies. Humans lacking the Duffy blood group antigens are also resistant to infection by Plasmodium vivax, a human malaria, indicating that this malaria also requires the Duffy antigen as a ligand for invasion [3]. Due to this requirement, P. vivax is absent from West Africa where almost all of the population is Duffy negative.We have recently identified a 135-kDa polypeptide synthesized by P. knowlesi asexual parasites which binds to the Duffy blood group antigen with receptor-like specificity [4]. We observed, using enzyme-treated erythrocytes, that binding of the 135-kDa polypeptide correlated with the ability of merozoites to invade these cells. In the present study, we demonstrate that fucoidan, a sulfated polysaccharide, and dextran sulfate, a glycosaminoglycan, specifically block the Cor...

Growth-inhibitory effect of a fucoidan from brown seaweed Undaria pinnatifida on Plasmodium parasites

“…In a different study, fucoidan could inhibit the invasion of human Duffy-positive and rhesus erythrocytes by Plasmodium knowlesi, analogous to the results reported in this study (Dalton et al 1991). This finding is consistent with that described in earlier reports which demonstrate that the inhibitory effect of fucoidan on the invasion can be simply considered as a result of nonspecific electrostatic interactions rather than a consequence of specific cytoadhesion receptors (Xiao et al 1996).…”

Suramin and Suramin Analogues Inhibit Merozoite Surface Protein-1 Secondary Processing and Erythrocyte Invasion by the Malaria Parasite Plasmodium falciparum

“…For example, merozoite invasion of erythrocytes and sporozoite invasion of hepatocytes are inhibited by sulfated glycans (11,12,(23)(24)(25), and suramin has been shown to inhibit invasion of HepG2 cells by P. falciparum sporozoites with an IC 50 of 50 M (11). The molecular targets of these agents are unclear, although the 135-kDa Duffy-binding ligand of Plasmodium knowlesi has been shown to bind to fucoidan (26), and TRAP (thrombospondin-related anonymous protein) has been implicated in the effects of suramin on sporozoite invasion (11).…”

Receptors for carbohydrate ligands including heparin on the cell surface of Leishmania and other trypanosomatids

“…Biochemical studies of isolated heparin-binding proteins have led to the conclusion that several members of this family are lectins, for example the heparin-binding protein from human placenta (Kohnke-Godt & Gabius 1989). T h e glycosaminoglycans used in this study to interfere with the binding of NGP,, and heparin have been described as inhibitors for isolated lectins o r for invasion assays (Kohnke-Godt & Gabius 1989;Dalton et al 1991).…”