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Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes both debilitating acute and chronic disease. Previous work has shown that type I interferons (IFNs) play a critical role in limiting CHIKV pathogenesis and that interferon alpha (IFN-α) and interferon beta (IFN-β) control acute CHIKV infection by distinct mechanisms. However, the role of type I IFNs, especially specific subtypes, during chronic CHIKV disease is unclear. To address this gap in knowledge, we evaluated chronic CHIKV pathogenesis in mice lacking IFN-α or IFN-β. We found that IFN-α was the dominant subtype that controls chronic disease. Despite detecting a varying type I IFN response throughout the course of disease, IFN-α acts within the first few days of infection to control the levels of persistent CHIKV RNA. In addition, using a novel CHIKV-3'-Cre tdTomato reporter system that fate maps CHIKV-infected cells, we showed that IFN-α limits the number of cells that survive CHIKV at sites of dissemination, particularly dermal fibroblasts and immune cells. Though myofibers play a significant role in CHIKV disease, they were not impacted by the loss of IFN-α. Our studies highlight that IFN-α and IFN-β play divergent roles during chronic CHIKV disease through events that occur early in infection and that not all cell types are equally dependent on type I IFNs for restricting viral persistence. IMPORTANCE Chikungunya virus (CHIKV) is a reemerging global pathogen with no effective vaccine or antiviral treatment for acute or chronic disease, and the mechanisms underlying chronic disease manifestations remain poorly defined. The significance of our research is in defining IFN-α, but not IFN-β, as an important host regulator of chronic CHIKV pathogenesis that acts within the first 48 hours of infection to limit persistent viral RNA and the number of cells that survive CHIKV infection 1 month post-infection. Loss of IFN-α had a greater impact on immune cells and dermal fibroblasts than myofibers, highlighting the need to delineate cell-specific responses to type I IFNs. Altogether, our work demonstrates that very early events of acute CHIKV infection influence chronic disease. Continued efforts to delineate early host-pathogen interactions may help stratify patients who are at risk for developing chronic CHIKV symptoms and identify therapeutics that may prevent progression to chronic disease altogether.

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response., (Copyright © 2019 American Society for Microbiology.)