Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

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 constit...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ilona Rissanen, Stefanie A. Krumm, Robert Stass, Annalis Whitaker, James E. Voss, Emily A. Bruce, Sylvia Rothenberger, Stefan Kunz, Dennis R. Burton, Juha T. Huiskonen, Jason W. Botten, Thomas A. Bowden, Katie J. Doores
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	glycoprotein hantavirus neutralizing antibody structure zoonosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1f67558141a14b57a4f6668f7781b182
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1f67558141a14b57a4f6668f7781b182
record_format	dspace
spelling	oai:doaj.org-article:1f67558141a14b57a4f6668f7781b1822021-11-10T18:37:52ZStructural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen10.1128/mBio.02531-202150-7511https://doaj.org/article/1f67558141a14b57a4f6668f7781b1822021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02531-20https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.Ilona RissanenStefanie A. KrummRobert StassAnnalis WhitakerJames E. VossEmily A. BruceSylvia RothenbergerStefan KunzDennis R. BurtonJuha T. HuiskonenJason W. BottenThomas A. BowdenKatie J. DooresAmerican Society for Microbiologyarticleglycoproteinhantavirusneutralizing antibodystructurezoonosisMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glycoprotein hantavirus neutralizing antibody structure zoonosis Microbiology QR1-502
spellingShingle	glycoprotein hantavirus neutralizing antibody structure zoonosis Microbiology QR1-502 Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
description	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. IMPORTANCE The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits. We isolated a neutralizing (HTN-Gn1) and a non-neutralizing (nnHTN-Gn2) monoclonal antibody and provide the first molecular-level insights into how the Gn glycoprotein may be targeted by the antibody-mediated immune response. These findings may guide rational vaccine design approaches focused on targeting the hantavirus glycoprotein envelope.
format	article
author	Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores
author_facet	Ilona Rissanen Stefanie A. Krumm Robert Stass Annalis Whitaker James E. Voss Emily A. Bruce Sylvia Rothenberger Stefan Kunz Dennis R. Burton Juha T. Huiskonen Jason W. Botten Thomas A. Bowden Katie J. Doores
author_sort	Ilona Rissanen
title	Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
title_short	Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
title_full	Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
title_fullStr	Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
title_full_unstemmed	Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen
title_sort	structural basis for a neutralizing antibody response elicited by a recombinant hantaan virus gn immunogen
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/1f67558141a14b57a4f6668f7781b182
work_keys_str_mv	AT ilonarissanen structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT stefanieakrumm structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT robertstass structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT annaliswhitaker structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT jamesevoss structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT emilyabruce structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT sylviarothenberger structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT stefankunz structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT dennisrburton structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT juhathuiskonen structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT jasonwbotten structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT thomasabowden structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen AT katiejdoores structuralbasisforaneutralizingantibodyresponseelicitedbyarecombinanthantaanvirusgnimmunogen
_version_	1718439756473303040

Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

Ejemplares similares