Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus.
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 tur...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-12-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1010142 |
| _version_ | 1819279278627356672 |
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| author | 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 Boyaka Chuan He Sun Hur Stefan Niewiesk Jianrong Li |
| author_facet | 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 Boyaka Chuan He Sun Hur Stefan Niewiesk Jianrong Li |
| author_sort | Miaoge Xue |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-24T00:25:22Z |
| format | Article |
| id | doaj.art-b173c27ab4264a278cb1cb7a1cbacf70 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-24T00:25:22Z |
| publishDate | 2021-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-b173c27ab4264a278cb1cb7a1cbacf702022-12-21T17:24:28ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-12-011712e101014210.1371/journal.ppat.1010142Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus.Miaoge XueYuexiu ZhangHaitao WangElizabeth L KairisMijia LuSadeem AhmadZayed AttiaOlivia HarderZijie ZhangJiangbo WeiPhylip ChenYouling GaoMark E PeeplesAmit SharmaProsper BoyakaChuan HeSun HurStefan NiewieskJianrong LiHuman 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.https://doi.org/10.1371/journal.ppat.1010142 |
| spellingShingle | 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 Boyaka Chuan He Sun Hur Stefan Niewiesk Jianrong Li Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. PLoS Pathogens |
| title | Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. |
| title_full | Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. |
| title_fullStr | Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. |
| title_full_unstemmed | Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. |
| title_short | Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus. |
| title_sort | viral rna n6 methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus |
| url | https://doi.org/10.1371/journal.ppat.1010142 |
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