Basal expression of interferon regulatory factor 1 drives intrinsic hepatocyte resistance to multiple RNA viruses

Nat Microbiol. 2019 Jul;4(7):1096-1104. doi: 10.1038/s41564-019-0425-6. Epub 2019 Apr 15.


Current models of cell-intrinsic immunity to RNA viruses centre on virus-triggered inducible antiviral responses initiated by RIG-I-like receptors or Toll-like receptors that sense pathogen-associated molecular patterns, and signal downstream through interferon regulatory factors (IRFs), transcription factors that induce synthesis of type I and type III interferons1. RNA viruses have evolved sophisticated strategies to disrupt these signalling pathways and evade elimination by cells, attesting to their importance2. Less attention has been paid to how IRFs maintain basal levels of protection against viruses. Here, we depleted antiviral factors linked to RIG-I-like receptor and Toll-like receptor signalling to map critical host pathways restricting positive-strand RNA virus replication in immortalized hepatocytes and identified an unexpected role for IRF1. We show that constitutively expressed IRF1 acts independently of mitochondrial antiviral signalling (MAVS) protein, IRF3 and signal transducer and activator of transcription 1 (STAT1)-dependent signalling to provide intrinsic antiviral protection in actinomycin D-treated cells. IRF1 localizes to the nucleus, where it maintains the basal transcription of a suite of antiviral genes that protect against multiple pathogenic RNA viruses, including hepatitis A and C viruses, dengue virus and Zika virus. Our findings reveal an unappreciated layer of hepatocyte-intrinsic immunity to these positive-strand RNA viruses and identify previously unrecognized antiviral effector genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Feces / virology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression*
  • Gene Knockout Techniques
  • Hepatocytes / immunology*
  • Hepatocytes / metabolism
  • Hepatocytes / virology
  • Humans
  • Immunity, Innate / genetics*
  • Interferon Regulatory Factor-1 / genetics*
  • Interferon Regulatory Factor-1 / metabolism
  • Kinetics
  • Liver / virology
  • Mice
  • RNA Viruses / physiology*
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Virus Replication


  • Interferon Regulatory Factor-1
  • RNA, Small Interfering