Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in P. falciparum placental sequestration
Open accessAbstract
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.
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Some sequence motifs on DBL3X were shown to be more likely to occur in parasites isolated from primigravidae than multigravidae.
“Nevertheless, a similar, but more restricted, process was observed in the expression of VAR2CSA molecules as some sequence motifs on DBL3X were shown to be more likely to occur in parasites isolated from primivs multigravidae (Dahlback et al. , 2006).”
From Towards a vaccine against pregnancy-associated malaria (2008) · cites this paper as Dahlback et al., 2006
Multiple var2csa alleles were found in field isolates.
“Although var2csa is structurally conserved between P. falciparum isolates and is consistently over-expresssed by placental isolates (Duffy et al. , 2006; Tuikue Ndam et al. , 2005), multiple var2csa alleles were found in field isolates (Dahlback et al. , 2006).”
From Towards a vaccine against pregnancy-associated malaria (2008) · cites this paper as Dahlback et al., 2006
Analysis of var2csa from field isolates has revealed alternating areas of substantial interclonal polymorphism.
“but analysis of var2csa from field isolates has revealed alternating areas of substantial interclonal polymorphism (Dahlback et al. , 2006; Trimnell et al. , 2006).”
From Towards a vaccine against pregnancy-associated malaria (2008) · cites this paper as Dahlback et al., 2006
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Multilaboratory Approach to Preclinical Evaluation of Vaccine Immunogens for Placental Malaria
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Can any lessons be learned from the ambiguous glycan binding of PfEMP1 domains?
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Progress and new horizons toward a VAR2CSA-based placental malaria vaccine
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- Authors
- Dahlbäck, M., Rask, T. S., Andersen, P. H., Nielsen, M. A., Ndam, N. T., Resende, M., Turner, L., Deloron, P., Hviid, L., Lund, O., Pedersen, A. G., Theander, T. G., & Salanti, A.
- Affiliations
- University of Copenhagen (DK)
- Technical University of Denmark (DK)
- Institut de Recherche pour le Développement (FR)
- Corresponding author
- Salanti, Ali
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006
- Volume
- 2
- Issue
- 11
- Pages
- e124
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC1636682
- OpenAlex
- W2073843808
- Cited by
- 98
- References
- 59
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- National Research Foundation
- Danmarks Grundforskningsfond
- Medical Research Council
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Keywords
- VAR2CSA, Plasmodium falciparum, malaria in pregnancy, placental sequestration, epitope mapping, sequence variation, diversifying selection, antibody accessibility, syncytiotrophoblast, chondroitin sulfate A, vaccine candidate, primigravida, multigravidae, peptide arrays, structural modeling
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Protozoan, Antigens, Protozoan, B-Lymphocytes, Binding, Competitive, Chondroitin Sulfates, Female, Humans, Models, Molecular, Molecular Sequence Data, Parity, Placenta, Plasmodium falciparum, Pregnancy, Receptors, Cell Surface, Recombinant Proteins, Recombination, Genetic, Genetic Variation, Molecular Structure, Protozoan Proteins, Malaria, Falciparum, Protein Structure, Tertiary, Epitope Mapping, Amino Acid Motifs
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