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 result in severe complications. Currently, there are no approved vaccines or treatments for OROV infection. We integrated clinical data from OROV-infected patients with human liver-derived organoid models to investigate the virus's impact on the liver and evaluate repurposed antivirals. Patient blood tests show elevated liver enzymes, suggesting 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 targeting viral RNA-dependent RNA polymerase, markedly inhibits OROV replication and mitigates virus-induced cytopathology. Combining molnupiravir with interferon-α resulted in synergistic antiviral activity, indicating the complementarity of virus-targeted and host-directed strategies.