Open AccessViral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus
Author(s) -
Miaoge Xue,
Yuexiu Zhang,
Haitao Wang,
Elizabeth L. Kairis,
Mijia Lu,
Sadeem Ahmad,
Zayed Attia,
Olivia Harder,
Zijie Zhang,
Jiangbo Wei,
Phylip Chen,
Youling Gao,
Mark E. Peeples,
Amit Sharma,
Prosper N. Boyaka,
Chuan He,
Sun Hur,
Stefan Niewiesk,
Jiànróng Lǐ
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010142
Subject(s) - innate immune system , biology , virology , irf3 , immune system , rig i , interferon , virus , acquired immune system , gene knockdown , immunity , mda5 , rna , rna interference , immunology , cell culture , gene , genetics , biochemistry
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.