3 years ago

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

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

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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31501-2

DOI: 10.1016/j.celrep.2017.10.054

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