Macrophage-augmented intestinal organoids model virus-host interactions in enteric viral diseases and facilitate therapeutic development
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.
Authors
- Jie Zhou (ORCID: https://orcid.org/0000-0002-2948-3873)
- Shijin Jiang (ORCID: https://orcid.org/0000-0002-4747-8410)
- Denis E. Kainov (ORCID: https://orcid.org/0000-0001-7716-6955)
- Ibrahim Ayada (ORCID: https://orcid.org/0000-0002-8197-3458)
- Marcel J. C. Bijvelds (ORCID: https://orcid.org/0000-0003-0814-188X)
- Valeria V. Orlova (ORCID: https://orcid.org/0000-0002-1169-2802)
- Francijna E. van den Hil (ORCID: https://orcid.org/0000-0002-9023-4390)
- Patrick P.C. Boor
- Guige Xu
- Wenshi Wang (ORCID: https://orcid.org/0000-0002-7330-262X)
- Qiuwei Pan (ORCID: https://orcid.org/0000-0001-9982-6184)
- Maikel Petrus Peppelenbosch (ORCID: https://orcid.org/0000-0001-9112-6028)
- Theano Tsikari
- Pengfei Li (ORCID: https://orcid.org/0000-0001-6436-4573)
- Yining Wang (ORCID: https://orcid.org/0000-0001-6441-2002)
- Jiajing Li (ORCID: https://orcid.org/0000-0001-5298-8637)
- Kuan Liu (ORCID: https://orcid.org/0000-0002-4874-141X)
- Annemarie C. de Vries
- Qin Fang (ORCID: https://orcid.org/0000-0003-4681-0060)
- Harry L.A. Janssen
- Dewy Mae Offermans
Institutions
- University Health Network (CA)
- Xuzhou Medical College (CN)
- Norwegian University of Science and Technology (NO)
- Sichuan University (CN)
- Leiden University Medical Center (NL)
- Toronto General Hospital (CA)
- Erasmus MC (NL)
- West China Hospital of Sichuan University (CN)
- Shandong Agricultural University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s41467-025-59639-9
- Citations
- 11
- Primary Topic
- Viral gastroenteritis research and epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 15.36
Funders
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek