Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations

Abstract

Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.

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

“…This will facilitate a more precise understanding of the significance of these antigens as targets of inhibitory antibodies. Antibodies raised in rabbits against EBA175, EBA140, PfRh1, and PfRh2b have been shown to inhibit invasion (13,17,40), further supporting their role as targets of acquired inhibitory antibodies. Antibodies raised in rabbits against PfRh4 did not inhibit invasion (20); lack of inhibitory activity may have resulted from the use of only small regions of the protein to generate antibodies.…”

“…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).…”

“…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.…”

Molecular and functional aspects of parasite invasion

“…EBA-140 does not bind to the altered form of glycophorin C in Ge-negative erythrocytes, nor can P. falciparum invade these cells using this invasion pathway. 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].…”

“…EBA-140 specifically binds to glycophorin C on red blood cells and this interaction contributes to invasion as antibodies to the ligand can partially inhibit the process [52,53]. Glycophorin C is responsible for the Gerbich (Ge) blood group system.…”