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

Aaron F. Carlin, Emily M. Plummer, Edward A. Vizcarra, Nicholas Sheets, Yunichel Joo, William Tang, Jeremy Day, Jay Greenbaum, Christopher K. Glass, Michael S. Diamond, Sujan Shresta

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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. Carlin et al. identify a non-canonical IRF-3-, IRF-5-, and IRF-7-independent antiviral defense mechanism that mediates protection against severe dengue disease. This alternative pathway utilizes IRF-1, predominantly via IL-12/IFN-γ, enabling survival in the context of reduced type I IFN responses.

Original languageEnglish
Pages (from-to)1600-1612
Number of pages13
JournalCell Reports
Volume21
Issue number6
DOIs
StatePublished - Nov 7 2017

Keywords

  • IFNs
  • IL-12
  • IRF-1
  • IRFs
  • dengue
  • flavivirus
  • innate immunity
  • interferon
  • macrophages
  • mouse models

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