title: Immunization with recombinant duffy binding-like-gamma3 induces pan-reactive and adhesion-blocking antibodies against placental chondroitin sulfate A-binding Plasmodium falciparum parasites.
abstract: Maternal malaria is associated with the sequestration, in the placenta, of Plasmodium falciparum-infected erythrocytes onto chondroitin sulfate A (CSA), via the duffy binding-like (DBL)-gamma3 domain of the P. falciparum erythrocyte membrane protein 1 (PfEMP1(CSA)) (DBL-gamma3(CSA)). The production of antibodies against CSA-binding infected erythrocytes (IEs(CSA)) is correlated with resistance to maternal malaria in multiparous women. We produced recombinant DBL-gamma3(CSA) (rDBL-gamma3(CSA)) in insect cells, corresponding to 2 variant DBL-gamma3(CSA) subtypes that mediate binding to CSA in laboratory lines and placental isolates. Both recombinant cysteine-rich DBL-gamma3(CSA) domains blocked IEs(CSA) binding to CSA. Immunization of mice, with the rDBL-gamma3(CSA)-FCR3 and rDBL-gamma3(CSA)-3D7 domains, resulted in the generation of antibodies recognizing homologous and heterologous rDBL-gamma3(CSA), a finding indicating conserved epitopes inducing a pan-reactive immune response. Mouse monoclonal antibodies (MAbs) against both recombinant proteins were pan-reactive with various IEs(CSA). One MAb efficiently inhibited and reversed IE(CSA) cytoadhesion to endothelial cells in vitro. Thus, DBL-gamma3(CSA) is the target of inhibitory and pan-reactive antibodies. Saimiri sciureus monkeys immunized with FCR3-rDBL-gamma3(CSA) developed pan-reactive and inhibitory antibodies, a finding suggesting that the development of a vaccine to prevent maternal malaria is feasible.
authors.affiliation: Unités de Parasitologie Expérimentale, Faculté de Médecine, Université de la Méditerranée (Aix-Marseille II), Marseille, France.
authors.forename: Fabio T M
authors.initials: FT
authors.lastname: Costa
authors.forename: Thierry
authors.initials: T
authors.lastname: Fusaï
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Yvon
authors.initials: Y
authors.lastname: Sterkers
authors.forename: Marylin
authors.initials: M
authors.lastname: Torrentino
authors.forename: Jean-Bernard Lekana
authors.initials: JB
authors.lastname: Douki
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traoré
authors.forename: Stéphane
authors.initials: S
authors.lastname: Petres
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.forename: Jürg
authors.initials: J
authors.lastname: Gysin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000913:Antibodies, Protozoan / Q000276:immunology / Q000494:pharmacology*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D005260:Female; D000882:Haplorhini / Q000276:immunology; D006801:Humans; D017780:Malaria Vaccines / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008969:Molecular Sequence Data; D010920:Placenta / Q000378:metabolism / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D011247:Pregnancy; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000302:isolation & purification
chemical_list: D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C066001:Duffy antigen binding protein, Plasmodium; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D002809:Chondroitin Sulfates