Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy.

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.