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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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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. |
format | Online Article Text |
id | pubmed-9231621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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