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Viral RNA N6-methyladenosine modification modulates both innate and adaptive immune responses of human respiratory syncytial virus.
Xue, Miaoge; Zhang, Yuexiu; Wang, Haitao; Kairis, Elizabeth L; Lu, Mijia; Ahmad, Sadeem; Attia, Zayed; Harder, Olivia; Zhang, Zijie; Wei, Jiangbo; Chen, Phylip; Gao, Youling; Peeples, Mark E; Sharma, Amit; Boyaka, Prosper; He, Chuan; Hur, Sun; Niewiesk, Stefan; Li, Jianrong.
Afiliação
  • Xue M; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Zhang Y; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Wang H; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
  • Kairis EL; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
  • Lu M; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Ahmad S; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Attia Z; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
  • Harder O; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
  • Zhang Z; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Wei J; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Chen P; Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, United States of America.
  • Gao Y; Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, United States of America.
  • Peeples ME; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
  • Sharma A; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Boyaka P; Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
  • He C; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
  • Hur S; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Niewiesk S; Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America.
  • Li J; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
PLoS Pathog ; 17(12): e1010142, 2021 12.
Article em En | MEDLINE | ID: mdl-34929018
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA Viral / Adenosina / Vírus Sincicial Respiratório Humano / Infecções por Vírus Respiratório Sincicial Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA Viral / Adenosina / Vírus Sincicial Respiratório Humano / Infecções por Vírus Respiratório Sincicial Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article