Recovery of adhesion to chondroitin-4-sulphate in Plasmodium falciparum varCSA disruption mutants by antigenically similar PfEMP1 variants.
Protection against maternal malaria has been associated with the acquisition of a specific antibody response that prevents adhesion of Plasmodium falciparum-infected erythrocytes to the glycosaminoglycan chondroitin-4-sulphate (CSA), which is present in the placental intervillous space. These antibodies are directed against variant forms of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) that mediate binding to CSA. We have generated insertional disruption mutants of the gene encoding the CSA-binding phenotype in the P. falciparum clone FCR3 (varCSA) to test the hypothesis that strategies targeting the parasite's determinant for this adhesive phenotype may prevent sequestration of infected erythrocytes in the placenta and hence the development of maternal malaria. The varCSA-disruption mutants were initially unable to adhere to CSA; however, they could recover the phenotype after repeated selection over CSA. We show that recovery of CSA binding is varCSA independent and mediated by the activation of a novel var variant. Importantly, the corresponding PfEMP1 protein reacts with a monoclonal antibody recognizing the DBL3 gamma domain of the varCSA gene product, indicating that the DBL3 gamma CSA-binding domains are conserved between these PfEMP1-binding variants. Our data support strategies exploring these conserved epitopes as vaccine candidates against maternal malaria.
Andrews
Katherine T
KT
Hygiene-Institut, Abteilung Parasitologie, Heidelberg, Germany.
Pirrit
Lindsay A
LA
Przyborski
Jude M
JM
Sanchez
Cecilia P
CP
Sterkers
Yvon
Y
Ricken
Sigrid
S
Wickert
Hannes
H
Lépolard
Catherine
C
Avril
Marion
M
Scherf
Artur
A
Gysin
Jürg
J
Lanzer
Michael
M
D000818:Animals; D000940:Antigenic Variation / Q000235:genetics*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D016466:CHO Cells; D002448:Cell Adhesion / Q000502:physiology*; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004730:Endothelium, Vascular / Q000166:cytology; D004912:Erythrocytes / Q000469:parasitology; D005434:Flow Cytometry; D018390:Gene Targeting; D006790:Host-Parasite Interactions; D006801:Humans; D008168:Lung / Q000166:cytology; D017780:Malaria Vaccines; D009710:Nucleotide Mapping; D010641:Phenotype; D010963:Plasmodium falciparum / Q000166:cytology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D011485:Protein Binding; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012453:Saimiri; D014162:Transfection; D014774:Virulence / Q000235:genetics
D000953:Antigens, Protozoan; D018955:CD36 Antigens; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D002809:Chondroitin Sulfates; D019765:Chondroitin ABC Lyase