title: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Maier
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
authors.forename: John C
authors.initials: JC
authors.lastname: Reeder
authors.forename: Sheral S
authors.initials: SS
authors.lastname: Patel
authors.forename: James W
authors.initials: JW
authors.lastname: Kazura
authors.forename: Peter A
authors.initials: PA
authors.lastname: Zimmerman
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D000818:Animals; D001789:Blood Group Antigens / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism* / Q000469:parasitology*; D005091:Exons; D006021:Glycophorins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum; D008542:Melanesia; D008565:Membrane Proteins; D010641:Phenotype; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic
chemical_list: D001789:Blood Group Antigens; D002352:Carrier Proteins; D006021:Glycophorins; D008565:Membrane Proteins; D015800:Protozoan Proteins; C451423:erythrocyte binding protein-2, Plasmodium falciparum