Human liver-derived organoids recapitulate Oropouche virus infection and manifestation, enabling antiviral drug discovery

Oropouche virus (OROV) is a neglected, re-emerging arbovirus that typically causes self-limiting febrile illness but can also lead to severe complications. With no approved vaccines or treatments available, we integrate clinical data with human liver-derived organoids to assess liver involvement in OROV infection and identify antiviral candidates through drug repurposing. Patient blood tests show elevated liver enzymes, indicating OROV-associated hepatic dysfunction. OROV isolates productively infect liver organoids and induce severe cellular damage. Transcriptomic profiling reveals strong virus-host interactions, including activation of interferon-stimulated genes and cell death pathways. Pharmacological inhibition of the interferon pathway enhances OROV replication, whereas treatment with therapeutic interferon-α suppresses the infection. Molnupiravir, a clinically approved antiviral drug targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α results in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies. These findings strengthen preparedness and response to OROV emergence.