Structural basis for a neutralizing antibody response elicited by a recombinant hantaan virus Gn immunogen

DOI: 10.1128/mBio.02531-20

Authors: Ilona Rissanen (Wellcome Centre for Human Genetics, University of Oxford; University of Helsinki) , Stefanie A. Krumm (King's College London) , Robert Stass (Wellcome Centre for Human Genetics, University of Oxford) , Annalis Whitaker (University of Vermont) , James E. Voss (The Scripps Research Institute) , Emily A. Bruce (University of Vermont) , Sylvia Rothenberger (Lausanne University Hospital; University of Lausanne) , Stefan Kunz (Lausanne University Hospital; University of Lausanne) , Dennis R. Burton (The Scripps Research Institute; Ragon Institute of MGH, Harvard, and MIT) , Juha T. Huiskonen (Wellcome Centre for Human Genetics, University of Oxford; University of Helsinki) , Jason W. Botten (University of Vermont) , Thomas A. Bowden (Wellcome Centre for Human Genetics, University of Oxford) , Katie J. Doores (King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio , VOL 146

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 19946 , 20223

Abstract: Hantaviruses are a group of emerging pathogens capable of causing severe disease upon zoonotic transmission to humans. The mature hantavirus surface presents higher-order tetrameric assemblies of two glycoproteins, Gn and Gc, which are responsible for negotiating host cell entry and constitute key therapeutic targets. Here, we demonstrate that recombinantly derived Gn from Hantaan virus (HTNV) elicits a neutralizing antibody response (serum dilution that inhibits 50% infection [ID50], 1:200 to 1:850) in an animal model. Using antigen-specific B cell sorting, we isolated monoclonal antibodies (mAbs) exhibiting neutralizing and non-neutralizing activity, termed mAb HTN-Gn1 and mAb nnHTN-Gn2, respectively. Crystallographic analysis reveals that these mAbs target spatially distinct epitopes at disparate sites of the N-terminal region of the HTNV Gn ectodomain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike supports the immune accessibility of the mAb HTN-Gn1 epitope, a hypothesis confirmed by electron cryo-tomography of the antibody with virus-like particles. These data define natively exposed regions of the hantaviral Gn that can be targeted in immunogen design.

Diamond Keywords: Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: I03-Macromolecular Crystallography , Krios I-Titan Krios I at Diamond

Added On: 19/07/2021 10:20

Documents:
mBio.02531-20.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Vaccines Structural biology

Technical Tags:

Diffraction Microscopy Macromolecular Crystallography (MX) Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)