Immunization with recombinant duffy binding-like-gamma3 induces pan-reactive and adhesion-blocking antibodies against placental chondroitin sulfate A-binding Plasmodium falciparum parasites.
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.
Costa
Fabio T M
FT
Unités de Parasitologie Expérimentale, Faculté de Médecine, Université de la Méditerranée (Aix-Marseille II), Marseille, France.
Fusaï
Thierry
T
Parzy
Daniel
D
Sterkers
Yvon
Y
Torrentino
Marylin
M
Douki
Jean-Bernard Lekana
JB
Traoré
Boubacar
B
Petres
Stéphane
S
Scherf
Artur
A
Gysin
Jürg
J
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
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