TY - JOUR

T1 - Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in P. falciparum placental sequestration

AU - Dahlbäck, Madeleine

AU - Rask, Thomas S

AU - Andersen, Pernille H

AU - Nielsen, Morten A

AU - Ndam, Nicaise T

AU - Resende, Mafalda

AU - Turner, Louise

AU - Deloron, Philippe

AU - Hviid, Lars

AU - Lund, Ole

AU - Pedersen, Anders Gorm

AU - Theander, Thor G

AU - Salanti, Ali

N1 - Keywords: Amino Acid Motifs; Amino Acid Sequence; Animals; Antibodies, Protozoan; Antigens, Protozoan; B-Lymphocytes; Binding, Competitive; Chondroitin Sulfates; Epitope Mapping; Female; Humans; Malaria, Falciparum; Models, Molecular; Molecular Sequence Data; Molecular Structure; Parity; Placenta; Plasmodium falciparum; Pregnancy; Protein Structure, Tertiary; Protozoan Proteins; Receptors, Cell Surface; Recombinant Proteins; Recombination, Genetic; Variation (Genetics)

PY - 2006

Y1 - 2006

N2 - Pregnancy-associated malaria is a major health problem, which mainly affects primigravidae living in malaria endemic areas. The syndrome is precipitated by accumulation of infected erythrocytes in placental tissue through an interaction between chondroitin sulphate A on syncytiotrophoblasts and a parasite-encoded protein on the surface of infected erythrocytes, believed to be VAR2CSA. VAR2CSA is a polymorphic protein of approximately 3,000 amino acids forming six Duffy-binding-like (DBL) domains. For vaccine development it is important to define the antigenic targets for protective antibodies and to characterize the consequences of sequence variation. In this study, we used a combination of in silico tools, peptide arrays, and structural modeling to show that sequence variation mainly occurs in regions under strong diversifying selection, predicted to form flexible loops. These regions are the main targets of naturally acquired immunoglobulin gamma and accessible for antibodies reacting with native VAR2CSA on infected erythrocytes. Interestingly, surface reactive anti-VAR2CSA antibodies also target a conserved DBL3X region predicted to form an alpha-helix. Finally, we could identify DBL3X sequence motifs that were more likely to occur in parasites isolated from primi- and multigravidae, respectively. These findings strengthen the vaccine candidacy of VAR2CSA and will be important for choosing epitopes and variants of DBL3X to be included in a vaccine protecting women against pregnancy-associated malaria.

AB - Pregnancy-associated malaria is a major health problem, which mainly affects primigravidae living in malaria endemic areas. The syndrome is precipitated by accumulation of infected erythrocytes in placental tissue through an interaction between chondroitin sulphate A on syncytiotrophoblasts and a parasite-encoded protein on the surface of infected erythrocytes, believed to be VAR2CSA. VAR2CSA is a polymorphic protein of approximately 3,000 amino acids forming six Duffy-binding-like (DBL) domains. For vaccine development it is important to define the antigenic targets for protective antibodies and to characterize the consequences of sequence variation. In this study, we used a combination of in silico tools, peptide arrays, and structural modeling to show that sequence variation mainly occurs in regions under strong diversifying selection, predicted to form flexible loops. These regions are the main targets of naturally acquired immunoglobulin gamma and accessible for antibodies reacting with native VAR2CSA on infected erythrocytes. Interestingly, surface reactive anti-VAR2CSA antibodies also target a conserved DBL3X region predicted to form an alpha-helix. Finally, we could identify DBL3X sequence motifs that were more likely to occur in parasites isolated from primi- and multigravidae, respectively. These findings strengthen the vaccine candidacy of VAR2CSA and will be important for choosing epitopes and variants of DBL3X to be included in a vaccine protecting women against pregnancy-associated malaria.

U2 - 10.1371/journal.ppat.0020124

DO - 10.1371/journal.ppat.0020124

M3 - Journal article

C2 - 17112315

VL - 2

SP - e124

JO - P L o S Pathogens

JF - P L o S Pathogens

SN - 1553-7366

IS - 11

ER -