Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus

Miaoge Xue, Boxuan Simen Zhao, Zijie Zhang, Mijia Lu, Olivia Harder, Phylip Chen, Zhike Lu, Anzhong Li, Yuanmei Ma, Yunsheng Xu, Xueya Liang, Jiyong Zhou, Stefan Niewiesk, Mark E. Peeples, Chuan He and Jianrong Li ()
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Miaoge Xue: The Ohio State University
Boxuan Simen Zhao: The University of Chicago
Zijie Zhang: The University of Chicago
Mijia Lu: The Ohio State University
Olivia Harder: The Ohio State University
Phylip Chen: The Research Institute at Nationwide Children’s Hospital
Zhike Lu: The University of Chicago
Anzhong Li: The Ohio State University
Yuanmei Ma: The Ohio State University
Yunsheng Xu: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou
Xueya Liang: The Ohio State University
Jiyong Zhou: Zhejiang University, Hangzhou
Stefan Niewiesk: The Ohio State University
Mark E. Peeples: The Research Institute at Nationwide Children’s Hospital
Chuan He: The University of Chicago
Jianrong Li: The Ohio State University

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12504-y

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