Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody
Abstract The intricate lattice of Gn and Gc glycoprotein spike complexes at the surface of hantaviruses facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Here, through study of a neutralizing monoclonal antibody (mAb 4G2) generated in a bank vole reservoir host following infection with Puumala virus (PUUV), we provide molecular-level insights into how antibody-mediated targeting of the hantaviral glycoprotein lattice effectively neutralizes the virus. Crystallographic analysis reveals that mAb 4G2 binds to a multi-domain site on Gc in the pre-fusion state, and that Fab binding is incompatible with the conformational changes of the Gc that are required for host cell entry. Cryo-electron microscopy of PUUV-like particles treated with Fab 4G2 demonstrates that the antibody binds to monomeric Gc at breaks in the Gn-Gc lattice, highlighting the immunological accessibility of Gc monomers on the mature hantavirus surface and the plastic nature of the higher-order lattice assembly. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses..
Medienart: |
Preprint |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
2021 |
Enthalten in: |
bioRxiv.org - (2021) vom: 15. Dez. Zur Gesamtaufnahme - year:2021 |
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Sprache: |
Englisch |
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Beteiligte Personen: |
Rissanen, Ilona [VerfasserIn] |
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Links: |
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doi: |
10.1101/2020.04.17.029876 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
XBI017601622 |
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520 | |a Abstract The intricate lattice of Gn and Gc glycoprotein spike complexes at the surface of hantaviruses facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Here, through study of a neutralizing monoclonal antibody (mAb 4G2) generated in a bank vole reservoir host following infection with Puumala virus (PUUV), we provide molecular-level insights into how antibody-mediated targeting of the hantaviral glycoprotein lattice effectively neutralizes the virus. Crystallographic analysis reveals that mAb 4G2 binds to a multi-domain site on Gc in the pre-fusion state, and that Fab binding is incompatible with the conformational changes of the Gc that are required for host cell entry. Cryo-electron microscopy of PUUV-like particles treated with Fab 4G2 demonstrates that the antibody binds to monomeric Gc at breaks in the Gn-Gc lattice, highlighting the immunological accessibility of Gc monomers on the mature hantavirus surface and the plastic nature of the higher-order lattice assembly. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses. | ||
700 | 1 | |a Stass, Robert |e verfasserin |4 aut | |
700 | 1 | |a Krumm, Stefanie A. |e verfasserin |4 aut | |
700 | 1 | |a Seow, Jeffrey |e verfasserin |4 aut | |
700 | 1 | |a Hulswit, Ruben J.G. |e verfasserin |4 aut | |
700 | 1 | |a Paesen, Guido C. |e verfasserin |4 aut | |
700 | 1 | |a Hepojoki, Jussi |e verfasserin |4 aut | |
700 | 1 | |a Vapalahti, Olli |e verfasserin |4 aut | |
700 | 1 | |a Lundkvist, Åke |e verfasserin |4 aut | |
700 | 1 | |a Reynard, Olivier |e verfasserin |4 aut | |
700 | 1 | |a Volchkov, Viktor |e verfasserin |4 aut | |
700 | 1 | |a Doores, Katie J. |e verfasserin |4 aut | |
700 | 1 | |a Huiskonen, Juha T. |e verfasserin |4 aut | |
700 | 1 | |a Bowden, Thomas A. |e verfasserin |4 aut | |
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