IFNα, but not IFNβ, acts early to control chronic chikungunya virus pathogenesis.

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes both debilitating acute and chronic disease. Previous work has shown that type I IFNs play a critical role in limiting CHIKV pathogenesis and that IFNα and IFNβ 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 IFNα or IFNβ. We found that the IFNαs were the dominant subtype that controls chronic disease. Despite detecting a varying type I IFN response throughout the course of disease, IFNα 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 IFNα 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 IFNα. Our studies highlight that IFNα and IFNβ 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 re-emerging 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 IFNα, but not IFNβ, 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 one month post infection. Loss of IFNα 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.