Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope

ABSTRACT Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoprote...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Brandyn R. West, Crystal L. Moyer, Liam B. King, Marnie L. Fusco, Jacob C. Milligan, Sean Hui, Erica Ollmann Saphire
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Bundibugyo virus Ebola virus antibody broadly neutralizing glycoprotein pan-ebolavirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5ac7f3a7134e439788c3a2f6d1f411d9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5ac7f3a7134e439788c3a2f6d1f411d9
record_format	dspace
spelling	oai:doaj.org-article:5ac7f3a7134e439788c3a2f6d1f411d92021-11-15T15:58:20ZStructural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope10.1128/mBio.01674-182150-7511https://doaj.org/article/5ac7f3a7134e439788c3a2f6d1f411d92018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01674-18https://doaj.org/toc/2150-7511ABSTRACT Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. The structures delineate the key protein and glycan contacts for binding that are conserved across the ebolaviruses, explain the antibody’s unique broad specificity and neutralization activity, and reveal the likely mechanism behind a known escape mutation in the fusion loop region of GP2. We found that the epitope of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion loop and then dips down into a highly conserved pocket beneath the N-terminal tail of GP2, a mode of recognition unlike any other antibody elicited against Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo virus glycoprotein, not previously visualized, is similar to the fold of Ebola virus GP, and ADI-15878 binds to each virus’s GP with a similar strategy and angle of attack. These findings will be useful in deployment of this antibody as a broad-spectrum therapeutic and in the design of immunogens that elicit the desired broadly neutralizing immune response against all members of the ebolavirus genus and filovirus family. IMPORTANCE There are five different members of the Ebolavirus genus. Provision of vaccines and treatments able to protect against any of the five ebolaviruses is an important goal of public health. Antibodies are a desired result of vaccines and can be delivered directly as therapeutics. Most antibodies, however, are effective against only one or two, not all, of these pathogens. Only one human antibody has been thus far described to neutralize all five ebolaviruses, antibody ADI-15878. Here we describe the molecular structure of ADI-15878 bound to the relevant target proteins of Ebola virus and Bundibugyo virus. We explain how it achieves its rare breadth of activity and propose strategies to design improved vaccines capable of eliciting more antibodies like ADI-15878.Brandyn R. WestCrystal L. MoyerLiam B. KingMarnie L. FuscoJacob C. MilliganSean HuiErica Ollmann SaphireAmerican Society for MicrobiologyarticleBundibugyo virusEbola virusantibodybroadly neutralizingglycoproteinpan-ebolavirusMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Bundibugyo virus Ebola virus antibody broadly neutralizing glycoprotein pan-ebolavirus Microbiology QR1-502
spellingShingle	Bundibugyo virus Ebola virus antibody broadly neutralizing glycoprotein pan-ebolavirus Microbiology QR1-502 Brandyn R. West Crystal L. Moyer Liam B. King Marnie L. Fusco Jacob C. Milligan Sean Hui Erica Ollmann Saphire Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
description	ABSTRACT Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. The structures delineate the key protein and glycan contacts for binding that are conserved across the ebolaviruses, explain the antibody’s unique broad specificity and neutralization activity, and reveal the likely mechanism behind a known escape mutation in the fusion loop region of GP2. We found that the epitope of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion loop and then dips down into a highly conserved pocket beneath the N-terminal tail of GP2, a mode of recognition unlike any other antibody elicited against Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo virus glycoprotein, not previously visualized, is similar to the fold of Ebola virus GP, and ADI-15878 binds to each virus’s GP with a similar strategy and angle of attack. These findings will be useful in deployment of this antibody as a broad-spectrum therapeutic and in the design of immunogens that elicit the desired broadly neutralizing immune response against all members of the ebolavirus genus and filovirus family. IMPORTANCE There are five different members of the Ebolavirus genus. Provision of vaccines and treatments able to protect against any of the five ebolaviruses is an important goal of public health. Antibodies are a desired result of vaccines and can be delivered directly as therapeutics. Most antibodies, however, are effective against only one or two, not all, of these pathogens. Only one human antibody has been thus far described to neutralize all five ebolaviruses, antibody ADI-15878. Here we describe the molecular structure of ADI-15878 bound to the relevant target proteins of Ebola virus and Bundibugyo virus. We explain how it achieves its rare breadth of activity and propose strategies to design improved vaccines capable of eliciting more antibodies like ADI-15878.
format	article
author	Brandyn R. West Crystal L. Moyer Liam B. King Marnie L. Fusco Jacob C. Milligan Sean Hui Erica Ollmann Saphire
author_facet	Brandyn R. West Crystal L. Moyer Liam B. King Marnie L. Fusco Jacob C. Milligan Sean Hui Erica Ollmann Saphire
author_sort	Brandyn R. West
title	Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
title_short	Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
title_full	Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
title_fullStr	Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
title_full_unstemmed	Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
title_sort	structural basis of pan-ebolavirus neutralization by a human antibody against a conserved, yet cryptic epitope
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/5ac7f3a7134e439788c3a2f6d1f411d9
work_keys_str_mv	AT brandynrwest structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT crystallmoyer structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT liambking structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT marnielfusco structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT jacobcmilligan structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT seanhui structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope AT ericaollmannsaphire structuralbasisofpanebolavirusneutralizationbyahumanantibodyagainstaconservedyetcrypticepitope
_version_	1718427030491496448

Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope

Ejemplares similares