Centers and Institutes
Published December 20, 2021 | Version v1
Journal article Open

Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus

Creators

  • 1. Ohio State University
  • 2. Harvard University
  • 3. University of Chicago
  • 4. Nationwide Children's Hospital

Description

Human respiratory syncytial virus (RSV) is the leading cause of respiratory tract infections in humans. A well-known challenge in the development of a live attenuated RSV vaccine is that interferon (IFN)-mediated antiviral responses are strongly suppressed by RSV nonstructural proteins which, in turn, dampens the subsequent adaptive immune responses. Here, we discovered a novel strategy to enhance innate and adaptive immunity to RSV infection. Specifically, we found that recombinant RSVs deficient in viral RNA N6-methyladenosine (m6A) and RSV grown in m6A methyltransferase (METTL3)-knockdown cells induce higher expression of RIG-I, bind more efficiently to RIG-I, and enhance RIG-I ubiquitination and IRF3 phosphorylation compared to wild-type virion RNA, leading to enhanced type I IFN production. Importantly, these m6A-deficient RSV mutants also induce a stronger IFN response in vivo, are significantly attenuated, induce higher neutralizing antibody and T cell immune responses in mice and provide complete protection against RSV challenge in cotton rats. Collectively, our results demonstrate that inhibition of RSV RNA m6A methylation enhances innate immune responses which in turn promote adaptive immunity.

Data availability

All relevant data are within the manuscript and its Supporting Information files.

Files

journal.ppat.1010142.pdf

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Additional details

Identifiers

DOI
10.1371/journal.ppat.1010142
Other
oai:uchicago.tind.io:5892

Funding

National Institutes of Health
R01 AI090060
National Institutes of Health
P01 AI112524
National Institutes of Health
R00 AI125136
National Institutes of Health
R01AI111784
National Institutes of Health
RM1 HG008935
National Institutes of Health
AI090060

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Chemistry
Center(s) or Institute(s)
Institute for Biophysical Dynamics