title: Identification of a 67-amino-acid region of the Plasmodium falciparum variant surface antigen that binds chondroitin sulphate A and elicits antibodies reactive with the surface of placental isolates.
abstract: The complications of malaria in pregnancy are caused by the massive sequestration of parasitized erythrocytes (PE) in the placenta. Placental isolates of Plasmodium falciparum are unusual in that they do not bind the primary microvasculature receptor CD36 but instead bind chondroitin sulphate A (CSA). Pregnant mothers develop antibodies that recognize placental variants worldwide, suggesting that a vaccine against malaria in pregnancy is possible. Some members of the Duffy binding-like gamma (DBL-gamma) domain of the large and diverse P. falciparum erythrocyte membrane protein-1 (PfEMP-1) family, when expressed on Chinese hamster ovary (CHO) cells, bind CSA. To characterize better the molecular requirements for DBL-gamma adhesion to CSA, we determined the binding of various DBL-gamma domains. Most DBL-gamma did not bind CSA, and no conserved region was identified that strictly differentiated binders from non-binders. Structure-function analysis of the FCR3-CSA DBL-gamma domain localized the minimal CSA binding region to a 67-residue fragment. This region was partially conserved among some binding sequences. Serum from a rabbit immunized with the minimal domain reacted with CSA-binding parasite lines, but not with non-CSA-adherent PE lines that adhered to CD36 and other receptors. The identification of a minimal binding region from a highly variable cytoadherent family may have application for a vaccine against malaria in pregnancy.
authors.affiliation: Laboratory of Molecular and Vector Research, NIAID, NIH, Bethesda, MD 20892-0425, USA. bgamain@pasteur.fr
authors.forename: Benoit
authors.initials: B
authors.lastname: Gamain
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.forename: Dror I
authors.initials: DI
authors.lastname: Baruch
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
authors.forename: Jurg
authors.initials: J
authors.lastname: Gysin
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000378:metabolism*; D017124:Conserved Sequence; D006224:Cricetinae; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000276:immunology* / Q000472:pathogenicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011817:Rabbits; D017385:Sequence Homology; D013329:Structure-Activity Relationship
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D018955:CD36 Antigens; D008565:Membrane Proteins; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D002809:Chondroitin Sulfates