Genome-wide RNA-seq transcriptional analysis of splenocyte responses to Dengue virus infection in WT, Irf3(-/-)×Irf7(-/-) (DKO), Irf3-/-xIrf5-/-xIrf7-/- (TKO), and Ifnar1-/- (AB6) mice.

Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that play critical roles in translating viral recognition into antiviral responses, including type I IFN production. Dengue virus (DENV) and other clinically important flaviviruses are controlled by functional type I interferon (IFN) responses. Using an experimental model of DENV infection that recapitulates key aspects of the human disease in mice, we demonstrate that while mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, mice that are deficient in IRF-3, IRF-5, and IRF-7 – the three transcription factors thought to regulate type I IFN production – survive DENV challenge. Genome-wide RNA-seq analysis of WT, Irf3(-/-)×Irf7(-/-) (DKO), Irf3-/-xIrf5-/-xIrf7-/- (TKO), and Ifnar1-/- (AB6) splenocytes identified minimal type I IFN production but a robust type II IFN (IFN-?) response in DKO and TKO mice later shown to be dependent on IRF-1. These results reveal a key role for IRF-1 in antiviral defense by activating both type I and II IFN responses during DENV infection. Overall design: RNA-seq of total splenocytes from WT, Irf3(-/-)×Irf7(-/-) (DKO), Irf3-/-xIrf5-/-xIrf7-/- (TKO), and Ifnar1-/- (AB6) mice either mock infected or infected with Dengue virus for 6 or 24 hours.