Jiajing Li, X. Wang, Yibo Ding, Fang Qin, Shirlene T.S. de Lima, Lito Papamichail, Rick Schraauwen, Julia Forato, Ingra M. Claro, Xinyi Hua, Leda M. Simões Mello, Dewy Mae Offermans, Monique M.A. Verstegen, Marjan Boter, Maikel P. Peppelenbosch, Anna Barbiero, Elisabetta Pagani, Harry L.A. Janssen, José A. Telmos Silva, M. J. T. F. dos Santos, Eder C. Pincinato, José Luiz Proenca-Modena, Pengfei Li, Adam A. Anas, Luc J.W. van der Laan, Concetta Castilletti, Bas B. Oude Munnink, William M. de Souza, Wenshi Wang, Qiuwei Pan
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.