Primary human intestinal organoids model enteric infection of monkeypox virus and enable scalable drug discovery

  • Sci Adv. 2026 Mar 27;12(13):eaea8280. doi: 10.1126/sciadv.aea8280.
Pengfei Li  1  2 ,  Xin Wang  2 ,  Jiangrong Zhou  2 ,  Yang Yao  3 ,  Yining Wang  2 ,  Guige Xu  2 ,  Rick Schraauwen  4 ,  Ana Maria Gonçalves da Silva  5 ,  Charlotte de Henau  6  7 ,  Roberto Incitti  8 ,  Dewy Mae Offermans  2 ,  Annemarie C de Vries  2 ,  Denis E Kainov  9 ,  Intikhab Alam  8 ,  Karine Raymond  6  7  10 ,  Amaro Nunes Duarte-Neto  5 ,  Marcel J C Bijvelds  2 ,  Qiuwei Pan  2
Affiliations
  • 1. Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.
  • 3. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4. Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.
  • 5. Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
  • 6. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
  • 7. The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, Netherlands.
  • 8. Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
  • 9. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway.
  • 10. University of Grenoble Alpes, CEA, Inserm, IRIG, UA13 BGE, Biomics, Grenoble, France.
PMID: 41894500 DOI: 10.1126/sciadv.aea8280
Abstract

Monkeypox virus (MPXV) infection-associated intestinal manifestations, including diarrhea and proctitis, have been frequently reported during mpox outbreaks. Here, we present clinical evidence that MPXV can directly infect the human intestine and induce lesions. Intriguingly, primary organoids cultured from human ileum and rectum support productive infections by MPXV strains from clade IIb, Ia, and Ib, which are responsible for the 2022-2023 global outbreak and concurrent outbreaks in Africa. Given that primary intestinal organoids can be rapidly expanded at large scale, we were able to screen a broad-spectrum Antiviral drug library. We identified 12 leading candidates of safe-in-human agents, including clinically used drugs such as clofarabine. We extensively validated the anti-MPXV activity of clofarabine in human intestinal and skin organoids, consistently demonstrating potent Antiviral activity against clade Ia, Ib, and IIb strains. These findings are important for better understanding the clinical manifestations of mpox. Primary intestinal organoid-based Infection models and the established Antiviral drug discovery pipeline bear major implications for responding to the current mpox global health emergency and sustaining epidemic poxvirus preparedness.

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