Modulating Chikungunya and Mayaro virus induced disease severity in mice using low concentrations of anti-IFNAR1 antibodies

Infectious disease research relies in large parts on in vivo models particularly for studying pathogenesis and preclinical studies. The laboratory mouse (Mus musculus) is the most widely used animal model, with a wide range of wild-type and genetically modified mouse strains available, though their accessibility and suitability may vary depending on the specific research objectives. Chikungunya virus (CHIKV), a mosquito-borne arthritogenic alphavirus, has emerged in various new regions and caused several millions of cases within the last decade. Mayaro virus (MAYV) and o’nyong-nyong virus (ONNV) are arthritogenic alphaviruses closely related to CHIKV, but each remains geographically restricted to a single region of the world. Mouse models for these viruses use either genetically modified immunodeficient mice resulting in lethal illness or footpad injection resulting in locally induced arthropathy. Here, we present a proof-of-concept study demonstrating how disease severity in mice can be modeled using sub-neutralizing concentrations of an interferon 1 receptor (IFNAR1) blocking monoclonal antibody (mAb). Seven weeks-old female C57BL/6 mice were intraperitoneally injected with varying anti-IFNAR1 antibody doses 24 or 48 hours before intraperitoneally infection with CHIKV, MAYV or ONNV. Viral loads in blood and clinical disease were evaluated the days following infection. For both CHIKV and MAYV, we observed a dose-dependent increase in disease severity with the administration of anti-IFNAR1 mAb. While a 1mg dose induced severe disease, a lower dose of 0.1mg resulted in moderate symptoms in mice, mainly facial pain expression signs, accompanied by detectable viremia in the days preceding symptom onset. We also demonstrated that viral loads in organs and serum concentrations of inflammatory cytokines and chemokines were increased for both viruses when animal received anti-IFNAR1 mAb. Finally, we observed that ONNV infection did not induce symptoms in mice, yet seroconversion occurred only in those receiving anti-IFNAR1 mAb, suggesting the antibody may increase susceptibility despite the low susceptibility of mice to ONNV. In conclusion, we provided the proof of concept that disease severity can be modulated using low concentrations of anti-IFNAR1 mAb. We employed this approach to develop a new mouse model for mild systemic CHIKV and MAYV disease. Using a widely accessible mouse strain, a commercial antibody and a common injection method this model can be easily implemented.