A Novel Erythrocyte Binding Antigen-175 Paralogue fromPlasmodium falciparum Defines a New Trypsin-resistant Receptor on Human Erythrocytes

Abstract

Plasmodium falciparum is the causative agent of the most lethal form of malaria in humans and is responsible for more than 2 million deaths per year. Because of the increasing resistance of this parasite toward the commonly used antimalarial drugs there is an urgent need for the development of a vaccine (1, 2). P. falciparum invades erythrocytes and develops and expands within this host cell followed by release of invasive merozoite forms into the blood stream. The merozoite is exposed to the host immune system, and proteins involved in the invasion process are potential vaccine candidates.

Molecular and functional aspects of parasite invasion

“…This suggests that Ge negativity has arisen in 50% of the Melanesian population through natural selection by severe malaria [52]. EBA-181 binds to a neuraminidase-sensitive and trypsin-resistant receptor [54] and might play a role in the glycophorin B-independent pathway described recently [55]. This paralog of EBA-175 also appears to be essential in some parasite lines, whereas in others its function is redundant [54].…”

“…EBA-181 binds to a neuraminidase-sensitive and trypsin-resistant receptor [54] and might play a role in the glycophorin B-independent pathway described recently [55]. This paralog of EBA-175 also appears to be essential in some parasite lines, whereas in others its function is redundant [54]. Indeed, the ability to disrupt EBA-181, EBA-175 and EBA-140 genetically in some P. falciparum parasite lines but not others suggests that a minimal number of ligands is required for functional merozoite invasion, most likely to provide sufficient affinity for binding of the parasite to the host cell.…”

Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

“…Invasion phenotypes can be broadly classified into 2 main groups: (a) sialic acid-dependent (SA-dependent) invasion, demonstrated by poor invasion of neuraminidase-treated erythrocytes (neuraminidase cleaves SA on the erythrocyte surface); and (b) SA-independent invasion, demonstrated by efficient invasion of neuraminidasetreated erythrocytes. SA-dependent (neuraminidase-sensitive) invasion involves the 3 EBAs and PfRh1, with EBA175 probably being the most important (11,13,15,17,19,24,28,29). These ligands bind to SA on the erythrocyte surface.…”

“…Secondary interactions are then required for activation of invasion processes. These involve 2 invasion ligand families: the erythrocyte-binding antigens (EBAs; EBA175, EBA140/BAEBL, EBA181/JESEBL) and P. falciparum reticulocyte-binding homolog (PfRh) proteins (PfRh1, -2a, -2b, and -4) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Additional members of these families, EBA165 and PfRh3, occur as pseudogenes (18,20,21).…”

“…EBA175 and EBA140 bind to glycophorin A (28)(29)(30) and C (13), respectively. EBA181 binds to SA on the erythrocyte surface and to band 4.1 protein (15,31). PfRh2b and PfRh4 are important in SA-independent invasion, and interactions appear chymotrypsin sensitive (16,20,32); however, receptors for binding these ligands are unknown.…”