Macrophage-augmented intestinal organoids model virus-host interactions in enteric viral diseases and facilitate therapeutic development

Guige Xu, Jiangrong Zhou, Kuan Liu, Yining Wang, Theano Tsikari, Fang Qin, Francijna Hil, Patrick P. C. Boor, Ibrahim Ayada, Annemarie C. Vries, Jiajing Li, Shijin Jiang, Dewy M. Offermans, Denis E. Kainov, Harry L. A. Janssen, Maikel P. Peppelenbosch, Marcel J. C. Bijvelds, Wenshi Wang, Valeria V. Orlova, Qiuwei Pan and Pengfei Li ()
Additional contact information
Guige Xu: Shandong Agricultural University
Jiangrong Zhou: Erasmus MC-University Medical Center
Kuan Liu: Erasmus MC-University Medical Center
Yining Wang: Erasmus MC-University Medical Center
Theano Tsikari: Leiden University Medical Center
Fang Qin: Xuzhou Medical University
Francijna Hil: Leiden University Medical Center
Patrick P. C. Boor: Erasmus MC-University Medical Center
Ibrahim Ayada: Erasmus MC-University Medical Center
Annemarie C. Vries: Erasmus MC-University Medical Center
Jiajing Li: Erasmus MC-University Medical Center
Shijin Jiang: Shandong Agricultural University
Dewy M. Offermans: Erasmus MC-University Medical Center
Denis E. Kainov: Norwegian University of Science and Technology
Harry L. A. Janssen: Erasmus MC-University Medical Center
Maikel P. Peppelenbosch: Erasmus MC-University Medical Center
Marcel J. C. Bijvelds: Erasmus MC-University Medical Center
Wenshi Wang: Xuzhou Medical University
Valeria V. Orlova: Leiden University Medical Center
Qiuwei Pan: Erasmus MC-University Medical Center
Pengfei Li: Erasmus MC-University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The pathogenesis of enteric viral infections is attributed to both viral replication and the resultant immune-inflammatory response. To recapitulate this complex pathophysiology, we engineer macrophage-augmented organoids (MaugOs) by integrating human macrophages into primary intestinal organoids. Echovirus 1, echovirus 6, rotavirus, seasonal coronavirus OC43 and SARS-CoV-2— known to directly invade the intestine— are used as disease modalities. We demonstrate that these viruses efficiently propagate in MaugOs and stimulate the host antiviral response. However, rotavirus, coronavirus OC43 and SARS-CoV-2, but not the two echoviruses, trigger inflammatory responses. Acetate, a microbial metabolite abundantly present in the intestine, potently inhibits virus-induced inflammatory responses in MaugOs, while differentially affecting viral replication in macrophages and organoids. Furthermore, we provide a proof-of-concept of combining antiviral agent with either anti-inflammatory regimen or acetate to simultaneously inhibit viral infection and inflammatory response in MaugOs. Collectively, these findings demonstrate that MaugOs are innovative tools for studying the complex virus-host interactions and advancing therapeutic development.

Date: 2025
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DOI: 10.1038/s41467-025-59639-9

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