Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus

N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m(6)A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of...

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Autores principales: Xue, Miaoge, Zhao, Boxuan Simen, Zhang, Zijie, Lu, Mijia, Harder, Olivia, Chen, Phylip, Lu, Zhike, Li, Anzhong, Ma, Yuanmei, Xu, Yunsheng, Liang, Xueya, Zhou, Jiyong, Niewiesk, Stefan, Peeples, Mark E., He, Chuan, Li, Jianrong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785563/
https://www.ncbi.nlm.nih.gov/pubmed/31597913
http://dx.doi.org/10.1038/s41467-019-12504-y
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author Xue, Miaoge
Zhao, Boxuan Simen
Zhang, Zijie
Lu, Mijia
Harder, Olivia
Chen, Phylip
Lu, Zhike
Li, Anzhong
Ma, Yuanmei
Xu, Yunsheng
Liang, Xueya
Zhou, Jiyong
Niewiesk, Stefan
Peeples, Mark E.
He, Chuan
Li, Jianrong
author_facet Xue, Miaoge
Zhao, Boxuan Simen
Zhang, Zijie
Lu, Mijia
Harder, Olivia
Chen, Phylip
Lu, Zhike
Li, Anzhong
Ma, Yuanmei
Xu, Yunsheng
Liang, Xueya
Zhou, Jiyong
Niewiesk, Stefan
Peeples, Mark E.
He, Chuan
Li, Jianrong
author_sort Xue, Miaoge
collection PubMed
description N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m(6)A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m(6)A methyltransferases decreases RSV replication and gene expression whereas knockdown of m(6)A demethylases has the opposite effect. The G gene transcript contains the most m(6)A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m(6)A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m(6)A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m(6)A methylation upregulates RSV replication and pathogenesis and identify viral m(6)A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.
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spelling pubmed-67855632019-10-11 Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus Xue, Miaoge Zhao, Boxuan Simen Zhang, Zijie Lu, Mijia Harder, Olivia Chen, Phylip Lu, Zhike Li, Anzhong Ma, Yuanmei Xu, Yunsheng Liang, Xueya Zhou, Jiyong Niewiesk, Stefan Peeples, Mark E. He, Chuan Li, Jianrong Nat Commun Article N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m(6)A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m(6)A methyltransferases decreases RSV replication and gene expression whereas knockdown of m(6)A demethylases has the opposite effect. The G gene transcript contains the most m(6)A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m(6)A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m(6)A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m(6)A methylation upregulates RSV replication and pathogenesis and identify viral m(6)A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses. Nature Publishing Group UK 2019-10-09 /pmc/articles/PMC6785563/ /pubmed/31597913 http://dx.doi.org/10.1038/s41467-019-12504-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xue, Miaoge
Zhao, Boxuan Simen
Zhang, Zijie
Lu, Mijia
Harder, Olivia
Chen, Phylip
Lu, Zhike
Li, Anzhong
Ma, Yuanmei
Xu, Yunsheng
Liang, Xueya
Zhou, Jiyong
Niewiesk, Stefan
Peeples, Mark E.
He, Chuan
Li, Jianrong
Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title_full Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title_fullStr Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title_full_unstemmed Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title_short Viral N(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
title_sort viral n(6)-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785563/
https://www.ncbi.nlm.nih.gov/pubmed/31597913
http://dx.doi.org/10.1038/s41467-019-12504-y
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