title: Fine specificity of Plasmodium vivax Duffy binding protein binding engagement of the Duffy antigen on human erythrocytes.
abstract: Plasmodium vivax invasion of human erythrocytes requires interaction of the P. vivax Duffy binding protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy binding is not well understood. To examine the relative contributions of the different subdomains to binding to Fy and their abilities to elicit strain-transcending binding-inhibitory antibodies, we evaluated recombinant proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy binding that could be the basis of a strain-transcending candidate vaccine against P. vivax.
authors.affiliation: Case Western Reserve University, Center for Global Health and Diseases, Cleveland, Ohio, USA.
authors.forename: Asim A
authors.initials: AA
authors.lastname: Siddiqui
authors.forename: Jia
authors.initials: J
authors.lastname: Xainli
authors.forename: Jesse
authors.initials: J
authors.lastname: Schloegel
authors.forename: Lenore
authors.initials: L
authors.lastname: Carias
authors.forename: Francis
authors.initials: F
authors.lastname: Ntumngia
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Casey
authors.forename: Michael
authors.initials: M
authors.lastname: Foley
authors.forename: John H
authors.initials: JH
authors.lastname: Adams
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D004375:Duffy Blood-Group System / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D010966:Plasmodium vivax / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*
chemical_list: C473745:ACKR1 protein, human; D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004375:Duffy Blood-Group System; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface