CoChat
Sign Up
Cited by 31Malaria Research and ControlBlood groups and transfusionVector-borne infectious diseases

Placental malaria vaccine candidate antigen VAR2CSA displays atypical domain architecture in some Plasmodium falciparum strains

Open access
Doritchamou, Justin Y. A., Morrison, Robert, Renn, Jonathan P., Ribeiro, Jose, Duan, Junhui, Fried, Michal, Duffy, Patrick E.·2019·Communications Biology
DOI 10.1038/s42003-019-0704-zPMC PMC6897902
Open this paper in CoChat — free accountOpen PDF

Abstract

Two vaccines based on Plasmodium falciparum protein VAR2CSA are currently in clinical evaluation to prevent placental malaria (PM), but a deeper understanding of var2csa variability could impact vaccine design. Here we identified atypical extended or truncated VAR2CSA extracellular structures and confirmed one extended structure in a Malian maternal isolate, using a novel protein fragment assembly method for RNA-seq and DNA-seq data. Extended structures included one or two additional DBL domains downstream of the conventional NTS-DBL1X-6ɛ domain structure, with closest similarity to DBLɛ in var2csa and non- var2csa genes. Overall, 4/82 isolates displayed atypical VAR2CSA structures. The maternal isolate expressing an extended VAR2CSA bound to CSA, but its recombinant VAR2CSA bound less well to CSA than VAR2CSA NF54 and showed lower reactivity to naturally acquired parity-dependent antibody. Our protein fragment sequence assembly approach has revealed atypical VAR2CSA domain architectures that impact antigen reactivity and function, and should inform the design of VAR2CSA-based vaccines.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s42003-019-0704-z

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 23

  1. [1]Desai M Epidemiology and burden of malaria in pregnancy Lancet Infect. Dis. 2007 7 93 104 10.1016/S1473-3099(07)70021-X 17251080 · DOI · Paper page
  2. [3]Salanti A Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria Mol. Microbiol. 2003 49 179 191 10.1046/j.1365-2958.2003.03570.x 12823820 · DOI · Paper page
  3. [5]Tuikue Ndam NG Variable adhesion abilities and overlapping antigenic properties in placental Plasmodium falciparum isolates J. Infect. Dis. 2004 190 2001 2009 10.1086/425521 15529266 · DOI
  4. [9]Bigey P The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A J. Infect. Dis. 2011 204 1125 1133 10.1093/infdis/jir499 21881129 · DOI · Paper page
  5. [10]Magistrado PA High efficacy of anti DBL4varepsilon-VAR2CSA antibodies in inhibition of CSA-binding Plasmodium falciparum-infected erythrocytes from pregnant women Vaccine 2011 29 437 443 10.1016/j.vaccine.2010.10.080 21075162 · DOI · Paper page
  6. [15]Kraemer SM Smith JD A family affair: var genes, PfEMP1 binding, and malaria disease Curr. Opin. Microbiol. 2006 9 374 380 10.1016/j.mib.2006.06.006 16814594 · DOI
  7. [16]Rask, T. S., Hansen, D. A., Theander, T. G., Gorm Pedersen, A. & Lavstsen, T. Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes–divide and conquer. PLoS Comput. Biol. 6 pii: e1000933 (2010). PMC2940729 20862303
  8. [17]Gangnard S Structural and immunological correlations between the variable blocks of the VAR2CSA domain DBL6epsilon from two Plasmodium falciparum parasite lines J. Mol. Biol. 2013 425 1697 1711 10.1016/j.jmb.2013.02.014 23429057 · DOI
  9. [18]Gangnard S Structure of the DBL3X-DBL4epsilon region of the VAR2CSA placental malaria vaccine candidate: insight into DBL domain interactions Sci. Rep. 2015 5 14868 10.1038/srep14868 26450557 PMC4598876 · DOI
  10. [19]Khunrae P Philip JM Bull DR Higgins MK Structural comparison of two CSPG-binding DBL domains from the VAR2CSA protein important in malaria during pregnancy J. Mol. Biol. 2009 393 202 213 10.1016/j.jmb.2009.08.027 19695262 PMC3778748 · DOI
  11. [20]Vigan-Womas I Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting PLoS Pathog. 2012 8 e1002781 10.1371/journal.ppat.1002781 22807674 PMC3395597 · DOI
  12. [21]Fried M Duffy PE Two DBLgamma subtypes are commonly expressed by placental isolates of Plasmodium falciparum Mol. Biochem. Parasitol. 2002 122 201 210 10.1016/S0166-6851(02)00103-2 12106874 · DOI · Paper page
  13. [22]Chene A Down-selection of the VAR2CSA DBL1-2 expressed in E. coli as a lead antigen for placental malaria vaccine development NPJ Vaccines 2018 3 28 10.1038/s41541-018-0064-6 30038803 PMC6050242 · DOI
  14. [23]Nielsen MA The influence of sub-unit composition and expression system on the functional antibody response in the development of a VAR2CSA based Plasmodium falciparum placental malaria vaccine PLoS ONE 2015 10 e0135406 10.1371/journal.pone.0135406 26327283 PMC4556615 · DOI
  15. [26]Mahamar A Host factors that modify Plasmodium falciparum adhesion to endothelial receptors Sci. Rep. 2017 7 13872 10.1038/s41598-017-14351-7 29066816 PMC5655674 · DOI
  16. [27]Vignali M NSR-seq transcriptional profiling enables identification of a gene signature of Plasmodium falciparum parasites infecting children J. Clin. Invest. 2011 121 1119 1129 10.1172/JCI43457 21317536 PMC3046638 · DOI
  17. [28]Lakshmanan V Cyclic GMP balance is critical for malaria parasite transmission from the mosquito to the mammalian host MBio 2015 6 e02330 10.1128/mBio.02330-14 25784701 PMC4453516 · DOI
  18. [29]Langmead B Salzberg SL Fast gapped-read alignment with Bowtie 2 Nat. Methods 2012 9 357 359 10.1038/nmeth.1923 22388286 PMC3322381 · DOI · Paper page
  19. [31]Zerbino DR Birney E Velvet: algorithms for de novo short read assembly using de Bruijn graphs Genome Res. 2008 18 821 829 10.1101/gr.074492.107 18349386 PMC2336801 · DOI
  20. [32]Ribeiro JM Chagas AC Pham VM Lounibos LP Calvo E An insight into the sialome of the frog biting fly, Corethrella appendiculata Insect Biochem. Mol. Biol. 2014 44 23 32 10.1016/j.ibmb.2013.10.006 24514880 PMC4035455 · DOI
  21. [33]Roy A Kucukural A Zhang Y I-TASSER: a unified platform for automated protein structure and function prediction Nat. Protoc. 2010 5 725 738 10.1038/nprot.2010.5 20360767 PMC2849174 · DOI
  22. [34]Dorin-Semblat D Phosphorylation of the VAR2CSA extracellular region is associated with enhanced adhesive properties to the placental receptor CSA PLoS Biol. 2019 17 e3000308 10.1371/journal.pbio.3000308 31181082 PMC6586358 · DOI
  23. [35]Doritchamou, J. et al. Functional antibodies against placental malaria parasites are variant dependent and differ by geographic region. Infect. Immun. 87 pii: e00865-18 (2019). PMC6589062 30988054

Cited by

Sorted by citations

Authors
Doritchamou, J. Y. A., Morrison, R., Renn, J. P., Ribeiro, J., Duan, J., Fried, M., & Duffy, P. E.
Affiliations
National Institutes of Health (US)
Corresponding author
Duffy, Patrick E.
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2019-12-06
Volume
2
Issue
1
Pages
457-457
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-019-0704-z
PMC
PMC6897902
OpenAlex
W2993773167
Cited by
31
References
9
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 5
FWCI
4.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | National Institutes of Health
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
  • Life Sciences › Immunology and Microbiology › Parasitology › Vector-borne infectious diseases
Keywords
placental malaria, VAR2CSA, Plasmodium falciparum, DBL domains, vaccine antigen design
MeSH terms
Protein Domains, Amino Acid Sequence, Antigens, Protozoan, Cell Membrane, Female, Humans, Placenta, Plasmodium falciparum, Pregnancy, Protein Conformation, Malaria, Falciparum, Databases, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review