1. Microbiology and Infectious Disease

Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes

  1. Abhishek Jamwal
  2. Cristina F Constantin
  3. Stephan Hirshi
  4. Sebastian Henrich
  5. Wolfgang Bildl
  6. Bernd Fakler
  7. Simon J Draper
  8. Uwe Schulte
  9. Matthew K Higgins  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University of Freiburg, Germany
https://doi.org/10.7554/eLife.83681
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Cite this article
  1. Abhishek Jamwal
  2. Cristina F Constantin
  3. Stephan Hirshi
  4. Sebastian Henrich
  5. Wolfgang Bildl
  6. Bernd Fakler
  7. Simon J Draper
  8. Uwe Schulte
  9. Matthew K Higgins
(2023)
Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes
eLife 12:e83681.
https://doi.org/10.7554/eLife.83681
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Abstract

Basigin is an essential host receptor for invasion of Plasmodium falciparum into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. Here we show that erythrocyte basigin is exclusively found in one of two macromolecular complexes, bound either to plasma membrane Ca2+-ATPase 1/4 (PMCA1/4) or to monocarboxylate transporter 1 (MCT1). PfRH5 binds to each of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca2+ export is not affected by PfRH5, making it unlikely that this is the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context.

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Article and author information

Author details

  1. Abhishek Jamwal

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.

  2. Cristina F Constantin

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.

  3. Stephan Hirshi

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.

  4. Sebastian Henrich

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    Sebastian Henrich, is affiliated with Roche Pharma AG. The author has no financial interests to declare..

  5. Wolfgang Bildl

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.

  6. Bernd Fakler

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    Bernd Fakler, is a shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis..

  7. Simon J Draper

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    Simon J Draper, is a named inventor on patents related to PfRH5-targeting antibodies.(PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9415-1357

  8. Uwe Schulte

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    Uwe Schulte, is an employee and shareholder of Logopharm GmbH and BF is shareholder of Logopharm GmbH. Logopharm GmbH produces ComplexioLyte 47 used in this study. The company provides ComplexioLyte reagents to academic institutions on a non-profit basis..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3557-0591

  9. Matthew K Higgins

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    For correspondence
    matthew.higgins@bioch.ox.ac.uk
    Competing interests
    Matthew K Higgins, is a named inventor on patents related to PfRH5-targeting antibodies.(PCT/GB2105/052205, PCT/GB2017/052608 and PCT/GB2019/052885)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2870-1955

Funding

Wellcome Trust (20797/Z/20/Z)

  • Abhishek Jamwal
  • Stephan Hirshi
  • Matthew K Higgins

Deutsche Forschungsgemeinschaft (SFB 746,TP 20)

  • Bernd Fakler

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: September 23, 2022
  2. Preprint posted: September 24, 2022 (view preprint)
  3. Accepted: October 4, 2023
  4. Accepted Manuscript published: October 5, 2023 (version 1)
  5. Version of Record published: October 12, 2023 (version 2)

Copyright

© 2023, Jamwal 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. Abhishek Jamwal
  2. Cristina F Constantin
  3. Stephan Hirshi
  4. Sebastian Henrich
  5. Wolfgang Bildl
  6. Bernd Fakler
  7. Simon J Draper
  8. Uwe Schulte
  9. Matthew K Higgins
(2023)
Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes
eLife 12:e83681.
https://doi.org/10.7554/eLife.83681

Share this article

https://doi.org/10.7554/eLife.83681

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