Lethal C57BL/6 mouse model for Yezo virus infection and antiviral therapeutic evaluation.

Yezo virus (YEZV) is an emerging tick-borne orthonairovirus that causes febrile illness and hepatic injury in humans. However, its pathogenesis and effective antiviral interventions remain poorly characterized. In this study, we generated a lethal, mouse-adapted YEZV strain through 30 serial passages in C57BL/6 mice. The adapted strain successfully recapitulated key clinical and pathological features of human YEZV infection, including leukopenia, thrombocytopenia, and hepatitis, as evidenced by elevated serum transaminases, high hepatic viral loads, and histopathological necroinflammatory lesions. Notably, female mice exhibited significantly higher mortality than males, revealing a sex-associated difference in disease susceptibility. Antiviral evaluation demonstrated that both favipiravir and ribavirin significantly suppressed in vivo YEZV replication, improved survival, and reduced hepatic viral burden. Collectively, this model establishes a rigorously validated platform for mechanistic studies of YEZV pathogenesis and the preclinical evaluation of antiviral therapeutics.