Oropouche virus causes acute hepatitis in mice controlled by type I interferons

family endemic to South America, is a current public health threat. The recent OROV outbreak driven by a novel reassortant strain has caused a dramatic increase in cases in 2024 (13,785 in Brazil, versus only 261 from 2015 to 2022) with sustained levels of transmission in 2025. Previously underreported outcomes have been recognized, including miscarriage, microcephaly, encephalitis, and death. OROV lethality in humans has been attributed to severe coagulopathy with liver involvement, and epidemiological data suggest that acute hepatitis occurs in mild cases of Oropouche fever, highlighting the underrecognized role of the liver in OROV pathogenesis. We present two discrete mouse models of OROV hepatic disease-a lethal model that is similar to the severe coagulative liver necrosis seen in fatal human cases and a model of self-resolving acute hepatitis, which is similar to mild human disease. In both models, OROV causes focal hepatic necrosis in mice, which progresses to massive necrosis and death when the Type I interferon receptor is antagonized. Additionally, we found that a contemporary OROV isolate is less pathogenic in mice than a historic prototypical strain. These studies enhance our understanding of OROV pathogenesis and provide additional models for potential therapeutic development and evaluation.IMPORTANCEThe disease burden of Oropouche fever has been underrecognized and underreported, as highlighted by the increased testing seen in an ongoing outbreak in South America. Specifically, the role of the liver in Oropouche virus pathogenesis has been understudied. Given the recent increase in cases and severe disease manifestations, there is a present need to understand Oropouche virus pathogenesis and provide models to test potential therapeutics. The mouse models of Oropouche-induced hepatitis presented here provide a means to understand how Oropouche virus causes liver damage in both a lethal and sublethal context. These models will be useful for the preclinical evaluation of vaccines and therapeutic treatments. Additionally, we compare the pathogenicity of a historical Oropouche virus isolate to a contemporary human isolate in a lethal mouse model.