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Emerging and reemerging tick-borne orthonairovirus infections (family Nairoviridae), which are genetically distinct from Crimean-Congo hemorrhagic fever virus, have been recently reported in East Asia. Here, we have established a mouse infection model using type-I/II interferon receptor-knockout mice (AG129) both for a better understanding the pathogenesis of these infections and validation of antiviral agents using Yezo virus (YEZV), a novel virus causing febrile illnesses associated with tick bites in Japan and China. YEZV-inoculated AG129 mice developed hepatitis with body weight loss and died by 6 days post infection. Blood biochemistry tests showed elevated liver enzyme levels, similar to YEZV-infected human patients. AG129 mice treated with favipiravir survived lethal YEZV infection, demonstrating the anti-YEZV effect of this drug. The present mouse model will help us better understand the pathogenicity of the emerging tick-borne orthonairoviruses and the development of specific antiviral agents for their treatment. Author summary: Establishment of animal models are pivotal in the study of newly emerging infectious diseases. In this report, we show that mice lacking interferon responses can serve as a lethal animal model for emerging tick-borne orthonairovirus infections. Yezo virus is a tick-borne orthonairovirus that is genetically distinct from previously reported human pathogenic orthonairoviruses such as Crimean-Congo Hemorrhagic fever virus, and has recently been reported to cause acute febrile illnesses in humans in Japan and China. Type-I/II interferon receptor-knockout mice (AG129 mice) infected with Yezo virus developed acute disease with elevated liver enzyme levels, including AST and ALT, similar to human patients. Our pathological and virological analyses in this mouse model revealed that Yezo virus mainly replicates in the liver and spleen and causes fatal hepatitis in AG129 mice. Furthermore, we could demonstrate the antiviral effect of favipiravir for Yezo virus infection. Thus, this animal model will facilitate studies of emerging tick-borne orthonairovirus infections which will allow a better understanding of disease pathogenesis and will permit the screening of potential antiviral agents. [ABSTRACT FROM AUTHOR]