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

Abstract

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.

Interleukin-17A Facilitates Chikungunya Virus Infection by Inhibiting IFN-α2 Expression

“…Supporting this hypothesis, we showed that the level of CHIKV is less in the infected cells in the presence of recombinant IFNA2. Consistent with the previous research that has demonstrated that type I IFN signaling is essential to mitigate CHIKV-induced pathogenicity in mice (9,62). Furthermore, we found that the infiltration of neutrophils into the footpads of Il17ra −/− mice was significantly reduced compared to WT mice on day 6 p.i.…”

“…Our results show the transcript levels of Isg-49 and Mx1 decrease in the presence of rIL-17A while increase in the presence of IL-17A neutralizing antibody during CHIKV infection, thus suggesting IL-17A directly or indirectly inhibits the ISG-49 and Mx1-mediated antiviral responses against CHIKV replication. Different IFN types may exert different functions during CHIKV infection, IFN-a limits early viral replication and dissemination; while IFN-b modulates neutrophil-mediated inflammation (62). Among IFN-a subtypes, IFN-a2 can be induced by Herpes Simplex Virus, Respiratory Syncytial Virus, and Newcastle Disease Virus (76).…”

Chikungunya Virus: An Emergent Arbovirus to the South American Continent and a Continuous Threat to the World

“… Cook et al (2019) recently showed distinct but synergistic roles for IFN-α and β in controlling CHIKV replication and disease. While IFN-α acts in non-hematopoietic cell types, reducing replication and early dissemination of CHIKV, IFN-β has a substantial impact on pathogenesis, since it can limit neutrophil-mediated inflammation at the site of infection ( Cook et al, 2019 ).…”

A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice

“…Type I IFN signaling in non-hematopoietic cells controls viral infection and foot swelling during CHIKV infections [58,59] and can modulate immune cell recruitment and activation [38]. An early type I IFN response could activate certain immune cells subsets (e.g., such as NK cells [60]) that clear virus infection while limiting immune-mediated pathogenesis.…”