title: Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in P. falciparum placental sequestration.
abstract: Pregnancy-associated malaria is a major health problem, which mainly affects primigravidae living in malaria endemic areas. The syndrome is precipitated by accumulation of infected erythrocytes in placental tissue through an interaction between chondroitin sulphate A on syncytiotrophoblasts and a parasite-encoded protein on the surface of infected erythrocytes, believed to be VAR2CSA. VAR2CSA is a polymorphic protein of approximately 3,000 amino acids forming six Duffy-binding-like (DBL) domains. For vaccine development it is important to define the antigenic targets for protective antibodies and to characterize the consequences of sequence variation. In this study, we used a combination of in silico tools, peptide arrays, and structural modeling to show that sequence variation mainly occurs in regions under strong diversifying selection, predicted to form flexible loops. These regions are the main targets of naturally acquired immunoglobulin gamma and accessible for antibodies reacting with native VAR2CSA on infected erythrocytes. Interestingly, surface reactive anti-VAR2CSA antibodies also target a conserved DBL3X region predicted to form an alpha-helix. Finally, we could identify DBL3X sequence motifs that were more likely to occur in parasites isolated from primi- and multigravidae, respectively. These findings strengthen the vaccine candidacy of VAR2CSA and will be important for choosing epitopes and variants of DBL3X to be included in a vaccine protecting women against pregnancy-associated malaria.
authors.affiliation: Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Dahlbäck
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Rask
authors.forename: Pernille H
authors.initials: PH
authors.lastname: Andersen
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.forename: Nicaise T
authors.initials: NT
authors.lastname: Ndam
authors.forename: Mafalda
authors.initials: M
authors.lastname: Resende
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.forename: Anders Gorm
authors.initials: AG
authors.lastname: Pedersen
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology; D001667:Binding, Competitive; D002809:Chondroitin Sulfates / Q000378:metabolism; D018604:Epitope Mapping; D005260:Female; D014644:Genetic Variation; D006801:Humans; D016778:Malaria, Falciparum / Q000503:physiopathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010298:Parity; D010920:Placenta / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000276:immunology*; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; C065668:erythrocyte-binding antigen 175, Plasmodium; D002809:Chondroitin Sulfates