In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 12 ( 2021-12-20), p. e1010142-
Abstract:
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 N 6 -methyladenosine (m 6 A) and RSV grown in m 6 A 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 m 6 A-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 m 6 A methylation enhances innate immune responses which in turn promote adaptive immunity.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010142
DOI:
10.1371/journal.ppat.1010142.g001
DOI:
10.1371/journal.ppat.1010142.g002
DOI:
10.1371/journal.ppat.1010142.g003
DOI:
10.1371/journal.ppat.1010142.g004
DOI:
10.1371/journal.ppat.1010142.g005
DOI:
10.1371/journal.ppat.1010142.g006
DOI:
10.1371/journal.ppat.1010142.g007
DOI:
10.1371/journal.ppat.1010142.g008
DOI:
10.1371/journal.ppat.1010142.g009
DOI:
10.1371/journal.ppat.1010142.g010
DOI:
10.1371/journal.ppat.1010142.g011
DOI:
10.1371/journal.ppat.1010142.s001
DOI:
10.1371/journal.ppat.1010142.s002
DOI:
10.1371/journal.ppat.1010142.s003
DOI:
10.1371/journal.ppat.1010142.s004
DOI:
10.1371/journal.ppat.1010142.s005
DOI:
10.1371/journal.ppat.1010142.s006
DOI:
10.1371/journal.ppat.1010142.s007
DOI:
10.1371/journal.ppat.1010142.s008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
Permalink