title: Functional and immunological characterization of the var2CSA-DBL5epsilon domain of a placental Plasmodium falciparum isolate.
abstract: Pregnancy-associated malaria (PAM) arises from sequestration of Plasmodium falciparum-parasitized erythrocytes (PE) in the placenta, leading to chronic symptoms in the expectant mother and serious consequences for fetal development. Placental sequestration has been linked to binding of chondroitin sulphate A (CSA) by the var2CSA variant of PfEMP1 expressed on the PE surface, and a substantial body of evidence shows that the immune response to var2CSA gives an effective protection against PAM. We have expressed the var2CSA-DBL5epsilon domain, derived from a placental isolate from Senegal, as soluble product in Escherichia coli and have shown using different criteria that the recombinant protein is obtained with the native conformation. Using surface plasmon resonance techniques, we have examined binding of DBL5epsilon to placental chondroitin sulphate proteoglycan and CSA; however, the recombinant protein also binds to other sulphated oligosaccharides, with higher affinity in some cases, indicating that the single domain lacks the specificity for CSA shown by the complete extra-cellular region of var2CSA and placental parasites. Recombinant DBL5epsilon was specifically recognized by sera from malaria-exposed Senegalese women in a parity-dependent manner but by sera not from children or males from the same endemic region. Conversely, DBL5epsilon induced antibodies in mice that recognized placental isolates from Benin but not isolates from children. The presence of universal epitopes thus supports DBL5epsilon as an interesting component of var2CSA to be considered for vaccine development.
authors.affiliation: Institut Pasteur, Unité d'Immunologie Structurale, CNRS URA2185, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gangnard
authors.forename: Nicaise G
authors.initials: NG
authors.lastname: Tuikue Ndam
authors.forename: Sedami
authors.initials: S
authors.lastname: Gnidehou
authors.forename: Michael
authors.initials: M
authors.lastname: Quiviger
authors.forename: Alexandre
authors.initials: A
authors.lastname: Juillerat
authors.forename: Grazyna
authors.initials: G
authors.lastname: Faure
authors.forename: Bruno
authors.initials: B
authors.lastname: Baron
authors.forename: Firmine
authors.initials: F
authors.lastname: Viwami
authors.forename: Philippe
authors.initials: P
authors.lastname: Deloron
authors.forename: Graham A
authors.initials: GA
authors.lastname: Bentley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology*; D001541:Benin; D002648:Child; D002675:Child, Preschool; D002809:Chondroitin Sulfates / Q000378:metabolism; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010920:Placenta / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000276:immunology* / Q000302:isolation & purification; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000469:parasitology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012675:Senegal; D016415:Sequence Alignment; D020349:Surface Plasmon Resonance
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D011994:Recombinant Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; D002809:Chondroitin Sulfates