STAT2 Mediates Innate Immunity to Dengue Virus in the Absence of STAT1 via the Type I Interferon Receptor

Abstract

Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50–100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo. Dengue virus (DENV) is a mosquito-borne pathogen present in the tropical and sub-tropical regions of the world, and an estimated 2.5 billion people are at risk of infection. Interferon (IFN) mediated innate responses in the host are critical for limiting viral spread following DENV infection. We have previously demonstrated that mice lacking STAT1, a key mediator of both type I and II IFN responses, are not susceptible to DENV-mediated disease. In this study, we sought to determine the mechanism responsible for protection against DENV disease in the absence of STAT1. Using knockout mice, we identify STAT2 as the protein that mediates type I IFN signaling during DENV infection in the absence of STAT1. The resulting antiviral response includes amplification of type I IFN and the expression of interferon stimulated genes. These data suggest DENV infection is especially sensitive to STAT2-mediated antiviral responses in vivo, and provide novel insights towards how IFNs protect against viral infections.