MicroRNA-302a suppresses influenza A virus-stimulated interferon regulatory factor-5 expression and cytokine storm induction

J Biol Chem. 2017 Dec 29;292(52):21291-21303. doi: 10.1074/jbc.M117.805937. Epub 2017 Oct 18.


During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3'-UTR of nuclear factor κB (NF-κB)-inducing kinase. In the current study, we found that miR-302a, another member of the miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knockout mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection up-regulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which down-regulated IRF-5 expression by binding its 3'-UTR. Moreover, IAV increased IRF-5 expression by down-regulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was down-regulated, whereas IRF-5 expression was up-regulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm.

Keywords: cytokine induction; cytokine storm; influenza virus; interferon regulatory factor (IRF); microRNA (miRNA); signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Disease Models, Animal
  • Dogs
  • Down-Regulation
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Immune Evasion
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza A Virus, H1N1 Subtype / metabolism
  • Influenza A Virus, H1N1 Subtype / physiology*
  • Influenza, Human / genetics
  • Influenza, Human / immunology
  • Influenza, Human / metabolism
  • Influenza, Human / virology
  • Interferon Regulatory Factors / biosynthesis*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology
  • Interferon Regulatory Factors / metabolism
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • MicroRNAs / metabolism
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / virology
  • Signal Transduction
  • Virus Replication


  • IRF5 protein, human
  • Interferon Regulatory Factors
  • MIRN302A microRNA, human
  • MicroRNAs
  • NF-kappa B