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Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus

Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the imm...

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Autores principales: Banerjee, Avik, Huang, Jiachen, Rush, Scott A., Murray, Jackelyn, Gingerich, Aaron D., Royer, Fredejah, Hsieh, Ching-Lin, Tripp, Ralph A., McLellan, Jason S., Mousa, Jarrod J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231621/
https://www.ncbi.nlm.nih.gov/pubmed/35696580
http://dx.doi.org/10.1073/pnas.2203326119
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author Banerjee, Avik
Huang, Jiachen
Rush, Scott A.
Murray, Jackelyn
Gingerich, Aaron D.
Royer, Fredejah
Hsieh, Ching-Lin
Tripp, Ralph A.
McLellan, Jason S.
Mousa, Jarrod J.
author_facet Banerjee, Avik
Huang, Jiachen
Rush, Scott A.
Murray, Jackelyn
Gingerich, Aaron D.
Royer, Fredejah
Hsieh, Ching-Lin
Tripp, Ralph A.
McLellan, Jason S.
Mousa, Jarrod J.
author_sort Banerjee, Avik
collection PubMed
description Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein.
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spelling pubmed-92316212022-12-13 Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus Banerjee, Avik Huang, Jiachen Rush, Scott A. Murray, Jackelyn Gingerich, Aaron D. Royer, Fredejah Hsieh, Ching-Lin Tripp, Ralph A. McLellan, Jason S. Mousa, Jarrod J. Proc Natl Acad Sci U S A Biological Sciences Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein. National Academy of Sciences 2022-06-13 2022-06-21 /pmc/articles/PMC9231621/ /pubmed/35696580 http://dx.doi.org/10.1073/pnas.2203326119 Text en Copyright © 2022 the Author(s). Published by PNAS https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Banerjee, Avik
Huang, Jiachen
Rush, Scott A.
Murray, Jackelyn
Gingerich, Aaron D.
Royer, Fredejah
Hsieh, Ching-Lin
Tripp, Ralph A.
McLellan, Jason S.
Mousa, Jarrod J.
Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title_full Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title_fullStr Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title_full_unstemmed Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title_short Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
title_sort structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231621/
https://www.ncbi.nlm.nih.gov/pubmed/35696580
http://dx.doi.org/10.1073/pnas.2203326119
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