An IRF-3-, IRF-5-, and IRF-7-Independent Pathway of Dengue Viral Resistance Utilizes IRF-1 to Stimulate Type I and II Interferon Responses

Cell Rep. 2017 Nov 7;21(6):1600-1612. doi: 10.1016/j.celrep.2017.10.054.

Abstract

Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that translate viral recognition into antiviral responses, including type I interferon (IFN) production. Dengue virus (DENV) and other clinically important flaviviruses are suppressed by type I IFN. While mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, we found that mice deficient in three transcription factors controlling type I IFN production (Irf3-/-Irf5-/-Irf7-/- triple knockout [TKO]) survive DENV challenge. DENV infection of TKO mice resulted in minimal type I IFN production but a robust type II IFN (IFN-γ) response. Using loss-of-function approaches for various molecules, we demonstrate that the IRF-3-, IRF-5-, IRF-7-independent pathway predominantly utilizes IFN-γ and, to a lesser degree, type I IFNs. This pathway signals via IRF-1 to stimulate interleukin-12 (IL-12) production and IFN-γ response. These results reveal a key antiviral role for IRF-1 by activating both type I and II IFN responses during DENV infection.

Keywords: IFNs; IL-12; IRF-1; IRFs; dengue; flavivirus; innate immunity; interferon; macrophages; mouse models.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Cells, Cultured
  • Dengue / mortality
  • Dengue / pathology*
  • Dengue / veterinary
  • Dengue / virology
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • Dengue Virus / physiology
  • Down-Regulation
  • Drug Resistance, Viral*
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Interferon Type I / metabolism*
  • Interferon-gamma / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology
  • Signal Transduction
  • Spleen / cytology
  • Spleen / metabolism
  • Spleen / virology
  • Up-Regulation
  • Virus Replication / drug effects

Substances

  • Antibodies
  • Antiviral Agents
  • Ifnar1 protein, mouse
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • Interferon Type I
  • Irf1 protein, mouse
  • Receptor, Interferon alpha-beta
  • Interferon-gamma