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

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作者
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
Jianrong Li
机构
[1] The Ohio State University,Department of Veterinary Biosciences, College of Veterinary Medicine
[2] The University of Chicago,Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics
[3] The Research Institute at Nationwide Children’s Hospital,Center for Vaccines and Immunity
[4] The First Affiliated Hospital of Wenzhou Medical University,Institute of Translational Medicine
[5] Wenzhou,College of Animal Sciences
[6] Zhejiang University,Department of Pediatrics
[7] Hangzhou,Howard Hughes Medical Institute
[8] The Ohio State University College of Medicine,undefined
[9] The University of Chicago,undefined
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Nature Communications | / 10卷
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摘要
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.
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