Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes
- University of Oxford, United Kingdom
- University of Freiburg, Germany
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.
Data availability
Data within graphs (source data) and uncropped gel and blot images are included with this submission
Article and author information
Author details
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
- Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France
Version history
- Received: September 23, 2022
- Preprint posted: September 24, 2022 (view preprint)
- Accepted: October 4, 2023
- Accepted Manuscript published: October 5, 2023 (version 1)
- 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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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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