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
Affiliations
Aaron F. Carlin
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
Emily M. Plummer
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Edward A. Vizcarra
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Nicholas Sheets
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Yunichel Joo
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
William Tang
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Jeremy Day
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Jay Greenbaum
Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA
Christopher K. Glass
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
Michael S. Diamond
Departments of Medicine, Pathology and Immunology, and Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Sujan Shresta
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, USA; Corresponding author
Summary: 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. Keywords: dengue, interferon, IFNs, IRF-1, IRFs, mouse models, macrophages, IL-12, innate immunity, flavivirus