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 Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arrang...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74707 |
| _version_ | 1828167898399506432 |
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| author | Juan Feng Xianchi Dong Adam DeCosta Yang Su Fiona Angrisano Katarzyna A Sala Andrew M Blagborough Chafen Lu Timothy A Springer |
| author_facet | Juan Feng Xianchi Dong Adam DeCosta Yang Su Fiona Angrisano Katarzyna A Sala Andrew M Blagborough Chafen Lu Timothy A Springer |
| author_sort | Juan Feng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:24:54Z |
| format | Article |
| id | doaj.art-dd90b1a1d2494b23848064d636afc1d3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:24:54Z |
| publishDate | 2021-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-dd90b1a1d2494b23848064d636afc1d32022-12-22T03:52:02ZengeLife Sciences Publications LtdeLife2050-084X2021-12-011010.7554/eLife.74707Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2Juan Feng0Xianchi Dong1Adam DeCosta2Yang Su3Fiona Angrisano4Katarzyna A Sala5Andrew M Blagborough6https://orcid.org/0000-0002-5257-8475Chafen Lu7https://orcid.org/0000-0002-3954-4836Timothy A Springer8https://orcid.org/0000-0001-6627-2904Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United StatesSchool of Life Sciences, Nanjing University, Nanjing, ChinaProgram in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United StatesProgram in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United StatesBurnet Institute, Melbourne, AustraliaDepartment of Pathology, University of Cambridge, Cambridge, United KingdomDepartment of Pathology, University of Cambridge, Cambridge, United KingdomBoston Children's Hospital, Boston, United StatesProgram in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United StatesHAP2 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.https://elifesciences.org/articles/74707HAP2malaria transmission-blocking vaccinemembrane fusiongamete fusogen |
| spellingShingle | Juan Feng Xianchi Dong Adam DeCosta Yang Su Fiona Angrisano Katarzyna A Sala Andrew M Blagborough Chafen Lu Timothy A Springer Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 eLife HAP2 malaria transmission-blocking vaccine membrane fusion gamete fusogen |
| title | Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 |
| title_full | Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 |
| title_fullStr | Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 |
| title_full_unstemmed | Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 |
| title_short | Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2 |
| title_sort | structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen hap2 |
| topic | HAP2 malaria transmission-blocking vaccine membrane fusion gamete fusogen |
| url | https://elifesciences.org/articles/74707 |
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