Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Immunity. 2005 Nov;23(5):465-78. doi: 10.1016/j.immuni.2005.09.016.

Abstract

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fibroblasts
  • Gene Expression Regulation
  • Humans
  • Interferons / immunology*
  • Interferons / metabolism*
  • Interleukin-1 Receptor-Associated Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / immunology*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Poly I-C / immunology
  • Signal Transduction
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 8 / agonists
  • Toll-Like Receptor 8 / immunology
  • Toll-Like Receptor 8 / metabolism
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism
  • Toll-Like Receptors / agonists
  • Toll-Like Receptors / immunology*
  • Toll-Like Receptors / metabolism*
  • Virus Diseases / immunology
  • Virus Diseases / metabolism
  • Virus Diseases / virology
  • Viruses / immunology*

Substances

  • TLR7 protein, human
  • TLR8 protein, human
  • TLR9 protein, human
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Interferons
  • Phosphotransferases (Alcohol Group Acceptor)
  • Interleukin-1 Receptor-Associated Kinases
  • Poly I-C