Interferon Regulatory Factor 1 Protects against Chikungunya Virus-Induced Immunopathology by Restricting Infection in Muscle Cells

Abstract

The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of alpha/beta interferon (IFN-α/β) (type I), IFN-γ (type II), and IFN-λ (type III). The transcription factor interferon regulatory factor 1 (IRF-1) has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN-stimulated genes (ISGs) and mediating signals downstream of IFN-γ. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role in vivo remains unknown. Here, we infected Irf1 ^-/- mice with two distantly related arthritogenic alphaviruses, chikungunya virus (CHIKV) and Ross River virus (RRV), and assessed the early antiviral functions of IRF-1 prior to induction of adaptive B and T cell responses. IRF-1 expression limited CHIKV-induced foot swelling in joint-associated tissues and prevented dissemination of CHIKV and RRV at early time points. Virological and histological analyses revealed greater infection of muscle tissues in Irf1 ^-/- mice than in wild-type mice. The antiviral actions of IRF-1 appeared to be independent of the induction of type I IFN or the effects of type II and III IFNs but were associated with altered local proinflammatory cytokine and chemokine responses and differential infiltration of myeloid cell subsets. Collectively, our in vivo experiments suggest that IRF-1 restricts CHIKV and RRV infection in stromal cells, especially muscle cells, and that this controls local inflammation and joint-associated swelling.IMPORTANCE Interferon regulatory factor 1 (IRF-1) is a transcription factor that regulates the expression of a broad range of antiviral host defense genes. In this study, using Irf1 ^-/- mice, we investigated the role of IRF-1 in modulating pathogenesis of two related arthritogenic alphaviruses, chikungunya virus and Ross River virus. Our studies show that IRF-1 controlled alphavirus replication and swelling in joint-associated tissues within days of infection. Detailed histopathological and virological analyses revealed that IRF-1 preferentially restricted CHIKV infection in cells of nonhematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint-associated tissues, which prevented immunopathology.

Keywords: Ross River virus; alphavirus; chikungunya virus; interferon; interferon regulatory factor 1; interferon-stimulated genes.