title: RH5-Basigin interaction plays a major role in the host tropism of Plasmodium falciparum.
abstract: Plasmodium falciparum, the cause of almost all human malaria mortality, is a member of the Laverania subgenus which infects African great apes. Interestingly, Laverania parasites exhibit strict host specificity in their natural environment: P. reichenowi, P. billcollinsi, and P. gaboni infect only chimpanzees; P. praefalciparum, P. blacklocki, and P. adleri are restricted to gorillas, and P. falciparum is pandemic in humans. The molecular mechanism(s) responsible for these host restrictions are not understood, although the interaction between the parasite blood-stage invasion ligand EBA175 and the host erythrocyte receptor Glycophorin-A (GYPA) has been implicated previously. We reexamined the role of the EBA175-GYPA interaction in host tropism using recombinant proteins and biophysical assays and found that EBA175 orthologs from the chimpanzee-restricted parasites P. reichenowi and P. billcollinsi both bound to human GYPA with affinities similar to that of P. falciparum, suggesting that the EBA175-GYPA interaction is unlikely to be the sole determinant of Laverania host specificity. We next investigated the contribution of the recently discovered Reticulocyte-binding protein Homolog 5 (RH5)-Basigin (BSG) interaction in host-species selectivity and found that P. falciparum RH5 bound chimpanzee BSG with a significantly lower affinity than human BSG and did not bind gorilla BSG, mirroring the known host tropism of P. falciparum. Using site-directed mutagenesis, we identified residues in BSG that are responsible for the species specificity of PfRH5 binding. Consistent with the essential role of the PfRH5-BSG interaction in erythrocyte invasion, we conclude that species-specific differences in the BSG receptor provide a molecular explanation for the restriction of P. falciparum to its human host.
authors.affiliation: Cell Surface Signalling Laboratory and Malaria Programme, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom.
authors.forename: Madushi
authors.initials: M
authors.lastname: Wanaguru
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006021:Glycophorins / Q000235:genetics / Q000378:metabolism; D006071:Gorilla gorilla; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D002679:Pan troglodytes; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000953:Antigens, Protozoan; C497886:BSG protein, human; D002352:Carrier Proteins; C409972:GYPA protein, human; D006021:Glycophorins; D015800:Protozoan Proteins; C531020:RH5 protein, Plasmodium falciparum; C065668:erythrocyte-binding antigen 175, Plasmodium; D051926:Basigin
keywords: protein interactions; surface plasmon resonance