A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA

Nat Immunol. 2006 Jan;7(1):40-8. doi: 10.1038/ni1282. Epub 2005 Nov 13.

Abstract

The innate immune system recognizes nucleic acids during infection or tissue damage; however, the mechanisms of intracellular recognition of DNA have not been fully elucidated. Here we show that intracellular administration of double-stranded B-form DNA (B-DNA) triggered antiviral responses including production of type I interferons and chemokines independently of Toll-like receptors or the helicase RIG-I. B-DNA activated transcription factor IRF3 and the promoter of the gene encoding interferon-beta through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-kappaB independent of both TBK and IKKi. IPS-1, an adaptor molecule linking RIG-I and TBK1, was involved in B-DNA-induced activation of interferon-beta and NF-kappaB. B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi. These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Chemokines / metabolism
  • DNA / immunology*
  • DNA, Bacterial / immunology
  • DNA, Viral / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Gene Expression / immunology
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / immunology
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • Toll-Like Receptors / immunology*
  • Transfection
  • Virus Diseases / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokines
  • DNA, Bacterial
  • DNA, Viral
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • MAVS protein, human
  • NF-kappa B
  • RNA, Messenger
  • Toll-Like Receptors
  • DNA
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase