Immunization with recombinant duffy binding-like-gamma3 induces pan-reactive and adhesion-blocking antibodies against placental chondroitin sulfate A-binding Plasmodium falciparum parasites

• Published in: The Journal of infectious diseases 2003-07, Vol.188 (1), p.153-164
• Main Authors: Costa, Fabio T M, Fusaï, Thierry, Parzy, Daniel, Sterkers, Yvon, Torrentino, Marylin, Douki, Jean-Bernard Lekana, Traoré, Boubacar, Petres, Stéphane, Scherf, Artur, Gysin, Jürg
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Protozoan - immunology; Antibodies, Protozoan - pharmacology; Antigens, Protozoan - chemistry; Antigens, Protozoan - immunology; Antigens, Protozoan - metabolism; Cell Adhesion - drug effects; Chondroitin Sulfates - chemistry; Chondroitin Sulfates - metabolism; Conserved Sequence; Female; Haplorhini - immunology; Humans; Malaria Vaccines - immunology; Malaria, Falciparum - immunology; Malaria, Falciparum - prevention & control; Mice; Molecular Sequence Data; Placenta - metabolism; Placenta - parasitology; Plasmodium falciparum - drug effects; Plasmodium falciparum - immunology; Plasmodium falciparum - metabolism; Pregnancy; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - immunology; Protozoan Proteins - metabolism; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Recombinant Proteins - immunology; Recombinant Proteins - isolation & purification
• ISSN: 0022-1899; 1537-6613

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.