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

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the o...

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Bibliographic Details
Published in:	eLife 2021-12, Vol.10
Main Authors:	Feng, Juan, Dong, Xianchi, DeCosta, Adam, Su, Yang, Angrisano, Fiona, Sala, Katarzyna A, Blagborough, Andrew M, Lu, Chafen, Springer, Timothy A
Format:	Article
Language:	eng
Subjects:	Animals Antibodies, Monoclonal - metabolism BASIC BIOLOGICAL SCIENCES Binding Sites, Antibody Biophysical Phenomena Culicidae - parasitology Disease transmission Electron microscopy Experiments Fab Fertilization gamete fusogen Germ Cells - immunology Germ Cells - physiology HAP2 Malaria Malaria - immunology Malaria - prevention & control Malaria - transmission malaria transmission-blocking vaccine Membrane Fusion Microbiology and Infectious Disease Monoclonal antibodies Mosquitoes Plasmodium Plasmodium berghei Plasmodium berghei - immunology Protein Binding Proteins Protozoan Proteins - chemistry Protozoan Proteins - immunology Protozoan Proteins - metabolism Structural Biology and Molecular Biophysics Vaccines
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Summary:	HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in 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 HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of 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 D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.
ISSN:	2050-084X 2050-084X