Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2
- Boston Children's Hospital, United States
- Nanjing University, China
- Burnet Institute, Australia
- 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.
Article and author information
Author details
Andrew M Blagborough
Timothy A Springer
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
- Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France
Version history
- Received: October 14, 2021
- Accepted: December 3, 2021
- Accepted Manuscript published: December 23, 2021 (version 1)
- Version of Record published: February 1, 2022 (version 2)
- 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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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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