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

Author

Listed:
  • 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
    The Ohio State University College of Medicine)

  • Chuan He

    (The University of Chicago
    The University of Chicago)

  • Jianrong Li

    (The Ohio State University)

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.

Suggested Citation

  • 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, 2019. "Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12504-y
    DOI: 10.1038/s41467-019-12504-y
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