4 years ago

Interferon regulatory factor-1 (IRF-1) protects against chikungunya virus induced immunopathology by restricting infection in muscle cells.

Poddar S, Nair S, Diamond MS, Shimak RM
The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of interferons (IFN)-α/β (type I), -γ (type II), and -λ (type III). The transcription factor interferon regulatory factor (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 (CHIKV) and Ross River (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 analysis revealed greater infection of muscle tissues in Irf1-/- compared to wild-type mice. The antiviral actions of IRF-1 appeared independent of the induction of type I IFN or effects of type II and III IFNs but were associated with altered local pro-inflammatory 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 this controls local inflammation and joint-associated swelling.IMPORTANCE Interferon regulatory factor (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 and Ross River viruses. 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 non-hematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint associated tissues, which prevented immunopathology.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28835505

DOI: PubMed:28835505

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