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

  • Cell Rep Med. 2026 Mar 17;7(3):102646. doi: 10.1016/j.xcrm.2026.102646.
Jiajing Li  1 ,  Xin Wang  1 ,  Yibo Ding  2 ,  Fang Qin  2 ,  Shirlene T S de Lima  3 ,  Lito Papamichail  4 ,  Rick Schraauwen  5 ,  Julia Forato  6 ,  Ingra M Claro  7 ,  Xinyi Hua  7 ,  Leda M Simões Mello  8 ,  Dewy Mae Offermans  1 ,  Monique M A Verstegen  9 ,  Marjan Boter  10 ,  Maikel P Peppelenbosch  1 ,  Anna Barbiero  11 ,  Elisabetta Pagani  12 ,  Harry L A Janssen  13 ,  José A Telmos Silva  14 ,  Magnun N N Dos Santos  15 ,  Eder C Pincinato  15 ,  José Luiz Proenca-Modena  6 ,  Pengfei Li  1 ,  Adam A Anas  16 ,  Luc J W van der Laan  9 ,  Concetta Castilletti  17 ,  Bas B Oude Munnink  10 ,  William M de Souza  18 ,  Wenshi Wang  19 ,  Qiuwei Pan  20
Affiliations
  • 1. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 2. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China.
  • 3. Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, USA; Laboratório Central de Saúde Pública do Ceará, Fortaleza, Brazil; Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.
  • 4. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 5. Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 6. Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil.
  • 7. Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, USA.
  • 8. Laboratório Central de Saúde Pública do Ceará, Fortaleza, Brazil.
  • 9. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 10. Department of Viroscience, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 11. Experimental and Clinical Medicine Department, University of Florence, Florence, Italy.
  • 12. Laboratory of Microbiology and Virology, Provincial Hospital of Bolzano (SABES-ASDAA), Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Bolzano, Italy.
  • 13. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
  • 14. Laboratório do Hospital da Mulher de Fortaleza, Fortaleza, Brazil.
  • 15. Department of Clinical Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil.
  • 16. Department of Medical Microbiology and Infectious Diseases, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Section of Infectious Diseases, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
  • 17. Department of Infectious-Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy.
  • 18. Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, USA. Electronic address: [email protected].
  • 19. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: [email protected].
  • 20. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address: [email protected].
PMID: 41806841 DOI: 10.1016/j.xcrm.2026.102646
Abstract

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.

Keywords
Oropouche emergence; liver; organoids; therapeutic discovery.
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