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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus

Miaoge Xue1, Boxuan Simen Zhao2, Zijie Zhang2

  • 1Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, 43210, USA.

Nature Communications
|October 11, 2019
PubMed

Insights

Viral RNA modification, N6-methyladenosine (m6A), boosts respiratory syncytial virus (RSV) replication and disease. Targeting m6A offers a new strategy for developing live attenuated RSV vaccines.

Area of Science:

  • Virology
  • Molecular Biology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) is a prevalent mRNA modification in eukaryotes.
  • The role of m6A in respiratory syncytial virus (RSV) replication and pathogenesis is largely unknown.

Purpose of the Study:

  • To investigate the impact of m6A modifications on RSV RNA.
  • To determine if m6A influences RSV replication and pathogenesis.
  • To explore the potential of targeting viral m6A for vaccine development.

Main Methods:

  • Analysis of m6A modification sites in RSV RNAs.
  • Manipulation of m6A levels using methyltransferase and demethylase knockdown.
  • Generation and characterization of recombinant RSV variants with altered m6A patterns.
  • Assessment of viral replication and pathogenesis in cell cultures and animal models.

Main Results:

  • RSV RNAs are modified by m6A in specific regions, enhancing viral replication and pathogenesis.
  • Decreased m6A levels (via methyltransferase knockdown) reduced RSV replication and gene expression.
  • Increased m6A levels (via demethylase knockdown) enhanced RSV replication.
  • RSV G gene transcripts exhibit the highest m6A modification.
  • RSV variants with reduced m6A in G transcripts showed attenuated replication but retained immunogenicity.

Conclusions:

  • Viral m6A methylation is a key regulator of RSV replication and pathogenesis.
  • m6A modification of RSV RNA presents a promising target for developing live attenuated vaccines.
  • This strategy may be applicable to other pneumoviruses.

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