Abstract

N6-methyladenosine (m6A) 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 m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m6A methyltransferases decreases RSV replication and gene expression whereas knockdown of m6A demethylases has the opposite effect. The G gene transcript contains the most m6A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m6A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m6A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.

Details

Title
Viral N 6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus
Author
Xue, Miaoge 1 ; Boxuan Simen Zhao 2 ; Zhang, Zijie 2   VIAFID ORCID Logo  ; Lu, Mijia 1 ; Harder, Olivia 1 ; Chen, Phylip 3 ; Lu, Zhike 2 ; Li, Anzhong 1 ; Ma, Yuanmei 1 ; Xu, Yunsheng 4 ; Liang, Xueya 1 ; Zhou, Jiyong 5   VIAFID ORCID Logo  ; Niewiesk, Stefan 1 ; Peeples, Mark E 6 ; He, Chuan 7   VIAFID ORCID Logo  ; Li, Jianrong 1 

1  Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA 
2  Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA 
3  Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA 
4  Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China 
5  College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, P. R. China 
6  Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA 
7  Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA 
Pages
1-18
Publication year
2019
Publication date
Oct 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-12504-y
ProQuest document ID
2303166427
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.