Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

Abstract

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.

Data availability

X-ray crystallography structures are accessible from theProtein Data Bank under PDB IDs: 7RLV (2F2 Fab-210-1), 7RLW (2F2 Fab-210-2), 7RLX (2F2 Fab-210-3), 7RLY (2F2 Fab-210-4), 7RLZ (2F2 Fab-210-5), 7RM1 (2E10.E9 Fab-247-2), 7RM3 (2E10.E9 Fab-247-3), 7RM0 (2E10.E9 Fab-247-4).

Article and author information

Author details

  1. Iga Kucharska

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6150-3419
  2. Lamia Hossain

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Danton Ivanochko

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Qiren Yang

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. John L Rubinstein

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0566-2209
  6. Régis Pomès

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3068-9833
  7. Jean-Philippe Julien

    Program in Molecular Medicine, The Hospital for Sick Children, Toronto, Canada
    For correspondence
    jean-philippe.julien@sickkids.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7602-3995

Funding

Canada Research Chairs

  • John L Rubinstein
  • Jean-Philippe Julien

Canadian Institutes of Health Research

  • Régis Pomès

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Aaron Frank, University of Michigan, United States

Version history

  1. Received: August 9, 2021
  2. Preprint posted: September 1, 2021 (view preprint)
  3. Accepted: January 12, 2022
  4. Accepted Manuscript published: January 13, 2022 (version 1)
  5. Version of Record published: February 2, 2022 (version 2)

Copyright

© 2022, Kucharska et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Iga Kucharska
  2. Lamia Hossain
  3. Danton Ivanochko
  4. Qiren Yang
  5. John L Rubinstein
  6. Régis Pomès
  7. Jean-Philippe Julien
(2022)
Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats
eLife 11:e72908.
https://doi.org/10.7554/eLife.72908

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https://doi.org/10.7554/eLife.72908

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