Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2

  1. Juan Feng
  2. Xianchi Dong
  3. Adam DeCosta
  4. Yang Su
  5. Fiona Angrisano
  6. Katarzyna A Sala
  7. Andrew M Blagborough
  8. Chafen Lu  Is a corresponding author
  9. Timothy A Springer  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Nanjing University, China
  3. Burnet Institute, Australia
  4. University of Cambridge, United Kingdom

Abstract

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

Data availability

Protein database accession IDs are 7LR3 for 2/6.14-Pb HAP2 D3 complex and 7LR4 for 2/1.12-Pb HAP2 D3 complex. Correspondence and requests for materials should be addressed to CL and TAS.

The following data sets were generated

Article and author information

Author details

  1. Juan Feng

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xianchi Dong

    School of Life Sciences, Nanjing University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam DeCosta

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yang Su

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Fiona Angrisano

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Katarzyna A Sala

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrew M Blagborough

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5257-8475
  8. Chafen Lu

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    For correspondence
    lu@crystal.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  9. Timothy A Springer

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    For correspondence
    springer@crystal.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6627-2904

Funding

National Institutes of Health (R01AI95686)

  • Chafen Lu
  • Timothy A Springer

Royal Society

  • Andrew M Blagborough

Kidder Fund

  • Timothy A Springer

Medical Research Council (MR/N00227X/1)

  • Andrew M Blagborough

Isaac Newton Trust

  • Andrew M Blagborough

Alborada Fund

  • Andrew M Blagborough

Wellcome Trust ISSF

  • Andrew M Blagborough

University of Cambridge JRG Scheme

  • Andrew M Blagborough

GHIT

  • Andrew M Blagborough

Rosetrees Trust

  • Andrew M Blagborough

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

Reviewing Editor

  1. Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France

Version history

  1. Received: October 14, 2021
  2. Accepted: December 3, 2021
  3. Accepted Manuscript published: December 23, 2021 (version 1)
  4. Version of Record published: February 1, 2022 (version 2)
  5. Version of Record updated: February 7, 2022 (version 3)

Copyright

© 2021, Feng 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. Juan Feng
  2. Xianchi Dong
  3. Adam DeCosta
  4. Yang Su
  5. Fiona Angrisano
  6. Katarzyna A Sala
  7. Andrew M Blagborough
  8. Chafen Lu
  9. Timothy A Springer
(2021)
Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2
eLife 10:e74707.
https://doi.org/10.7554/eLife.74707

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https://doi.org/10.7554/eLife.74707