A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity

Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20446-51. doi: 10.1073/pnas.0810372105. Epub 2008 Dec 11.


A conundrum of innate antiviral immunity is how nucleic acid-sensing Toll-like receptors (TLRs) and RIG-I/MDA5 receptors cooperate during virus infection. The conventional wisdom has been that the activation of these receptor pathways evokes type I IFN (IFN) responses. Here, we provide evidence for a critical role of a Toll-like receptor 3 (TLR3)-dependent type II IFN signaling pathway in antiviral innate immune response against Coxsackievirus group B serotype 3 (CVB3), a member of the positive-stranded RNA virus family picornaviridae and most prevalent virus associated with chronic dilated cardiomyopathy. TLR3-deficient mice show a vulnerability to CVB3, accompanied by acute myocarditis, whereas transgenic expression of TLR3 endows even type I IFN signal-deficient mice resistance to CVB3 and other types of viruses, provided that type II IFN signaling remains intact. Taken together, our results indicate a critical cooperation of the RIG-I/MDA5-type I IFN and the TLR3-type II IFN signaling axes for efficient innate antiviral immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • Enterovirus / immunology
  • Immunity, Innate*
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Interferon-Induced Helicase, IFIH1
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Knockout
  • Myocarditis / immunology
  • Myocarditis / virology
  • Signal Transduction / immunology*
  • Toll-Like Receptor 3 / deficiency
  • Toll-Like Receptor 3 / immunology*
  • Toll-Like Receptor 3 / metabolism
  • Virus Diseases / immunology*


  • Interferon Type I
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Interferon-gamma
  • Ddx58 protein, mouse
  • Ifih1 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1