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

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

bioRxiv.org - (2021) vom: 15. Dez. Zur Gesamtaufnahme - year:2021

Sprache:

Englisch

Beteiligte Personen:

Rissanen, Ilona [VerfasserIn]
Stass, Robert [VerfasserIn]
Krumm, Stefanie A. [VerfasserIn]
Seow, Jeffrey [VerfasserIn]
Hulswit, Ruben J.G. [VerfasserIn]
Paesen, Guido C. [VerfasserIn]
Hepojoki, Jussi [VerfasserIn]
Vapalahti, Olli [VerfasserIn]
Lundkvist, Åke [VerfasserIn]
Reynard, Olivier [VerfasserIn]
Volchkov, Viktor [VerfasserIn]
Doores, Katie J. [VerfasserIn]
Huiskonen, Juha T. [VerfasserIn]
Bowden, Thomas A. [VerfasserIn]

Links:

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doi:

10.1101/2020.04.17.029876

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

XBI017601622