Distinct Roles of Interferon Alpha and Beta in Controlling Chikungunya Virus Replication and Modulating Neutrophil-Mediated Inflammation

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-beta (IFN-beta knockout [IFN-beta-KO] mice or mice treated with an IFN-beta-blocking antibody) or IFN-alpha (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-alpha-blocking antibody). Mice lacking either IFN-alpha or IFN-beta 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-alpha sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-beta-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-beta had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-beta-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-alpha limiting early viral replication and dissemination and IFN-beta 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-alpha and IFN-beta both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-alpha limits CHIKV replication and dissemination, whereas IFN-beta 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.