Epitope Mapping and Topographic Analysis of VAR2CSA DBL3X Involved in P. falciparum Placental Sequestration

PLoS Pathogens

Thor G Theander¹  Thomas S Rask¹  Pernille H Andersen¹  Anders Gorm Pedersen¹  Morten A Nielsen²  Madeleine Dahlbäck²  Ole Lund²  Nicaise T Ndam²  Louise Turner²  Ali Salanti²  Philippe Deloron²  Mafalda Resende³  Lars Hviid³ 

[1] Center for Biological Sequence Analysis, BioCentrum, Technical University of Denmark, Kongens Lyngby, Denmark;Centre for Medical Parasitology, University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark;Institut de Recherche pour le Développement, Faculté de Pharmacie, Paris, France

关键词: Sequence motif analysis;    Antibodies;    Sequence alignment;    Sequence databases;    Malarial parasites;    Parasitic diseases;    Red blood cells;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.0020124

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 α-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.

【 授权许可】

CC BY