Erythrocyte glycophorins as receptors for Plasmodium merozoites

Abstract

Glycophorins are heavily glycosylated sialoglycoproteins of human and animal erythrocytes. In humans, there are four glycophorins: A, B, C and D. Glycophorins play an important role in the invasion of red blood cells (RBCs) by malaria parasites, which involves several ligands binding to RBC receptors. Four Plasmodium falciparum merozoite EBL ligands have been identified: erythrocyte-binding antigen-175 (EBA-175), erythrocyte-binding antigen-181 (EBA-181), erythrocyte-binding ligand-1 (EBL-1) and erythrocyte-binding antigen-140 (EBA-140). It is generally accepted that glycophorin A (GPA) is the receptor for P. falciparum EBA-175 ligand. It has been shown that α(2,3) sialic acid residues of GPA O-glycans form conformation-dependent clusters on GPA polypeptide chain which facilitate binding. P. falciparum can also invade erythrocytes using glycophorin B (GPB), which is structurally similar to GPA. It has been shown that P. falciparum EBL-1 ligand binds to GPB. Interestingly, a hybrid GPB-GPA molecule called Dantu is associated with a reduced risk of severe malaria and ameliorates malaria-related morbidity. Glycophorin C (GPC) is a receptor for P. falciparum EBA-140 ligand. Likewise, successful binding of EBA-140 depends on sialic acid residues of N- and O-linked oligosaccharides of GPC, which form a cluster or a conformational structure depending on the presence of peptide fragment encompassing amino acids (aa) 36–63. Evaluation of the homologous P. reichenowi EBA-140 unexpectedly revealed that the chimpanzee homolog of human glycophorin D (GPD) is probably the receptor for this ligand. In this review, we concentrate on the role of glycophorins as erythrocyte receptors for Plasmodium parasites. The presented data support the long-lasting idea of high evolutionary pressure exerted by Plasmodium on the human glycophorins, which emerge as important receptors for these parasites.

Valid Presumption of Shiga Toxin-Mediated Damage of Developing Erythrocytes in EHEC-Associated Hemolytic Uremic Syndrome

“…RBCs can be harmed by infectious microorganisms and pathogen-released toxic compounds, resulting in hemolysis and associated hemolytic anemia. The invasion of RBCs by Plasmodium falciparum , the best known and most serious form of malaria, involves several erythrocyte-binding ligands of the heavily glycosylated glycophorins A, B, C, and D [ 107 , 108 ]. High rates of parasitemia in which >10% of RBCs are parasitized may cause significant hemolysis and anemia.…”

Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

“…Binding of specific membrane sialoglycoproteins is the first step in the adsorption of pathogens on host cell membranes and further colonization of tissues and organs. This process has been confirmed in bacterial (Escherichia coli, Streptococcus suis), viral (influenza, Cardiovirus, Paramyxovirus), and protozoan (Plasmodium falciparum) infections [30][31][32][33][34][35]. Sialoglycans, especially sialo-Lewis a,b,x,y epitopes, play a crucial role in the interaction with selectins, which are the molecular basis of adhesion processes linked to the migration of immune cells to the target organs through the vascular endothelium and outside the circulatory system.…”

Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion

“…These six regions are followed by a transmembrane region keeping it anchored to merozoite membrane and a small cytoplasmatic tail ( Figure 4 B). EBA-175 binds to the host receptor glycophorin A (GPA) ( Figure 4 B and Figure 6 B) [ 95 , 96 ] which is resistant to enzyme treatment with chymotrypsin and susceptible to neuraminidase (cleaves sialic acid ligated to glycophorin’s oligosaccharide α-chains) [ 97 , 98 , 99 , 100 ]. The EBA-175-GPA interaction has a well-defined role in anchoring the parasite during erythrocyte invasion moving from merozoite apical end to their posterior end.…”

“…The dimer’s interface contains six glycan-binding sites, four located inside the channel, and two exposed in a cavity on the external surface. All six glycans contact residues from both RII monomers ( Figure 6 B–D), indicating that EBA-175 dimerization is biologically important for receptor binding and RBC invasion [ 95 , 97 , 100 ].…”

“…Peptides comprising aa 1085–1096 contain the erythrocyte binding site and have strongly inhibited parasite invasion [ 105 ]. It has been hypothesized that EBA-175 takes part in the second step of two-step erythrocyte binding to explain the presence of other regions [ 97 ]. Moreover, RII binding to GPA and Neu5Ac(2–3)Gal showed similar affinity, whereas the full-length EBA-175 ectodomain bound GPA with two-fold higher affinity than glycan alone [ 31 ].…”