Liu Kuan, Wang Yining, Li Jiajing, Zhou Jiahua, da Silva Ana Maria Gonçalves, Suñer Clara, Dai Zhe, Schraauwen Rick, Boor Patrick P C, Ober-Vliegen Kimberley, van den Hil Francijna, Offermans Dewy M, Tsikari Theano, Ayada Ibrahim, Peppelenbosch Maikel P, van Royen Martin E, Verstegen Monique M A, Wang Yijin, Orkin Chloe M, Janssen Harry L A, Orlova Valeria V, Li Pengfei, Mitjà Oriol, Duarte-Neto Amaro Nunes, van der Laan Luc J W, Pan Qiuwei
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Nat Biomed Eng. 2025 Jun 13. doi: 10.1038/s41551-025-01417-5.
The pathophysiology of acute viral diseases is complex. It is characterized by strong inflammatory responses driven by immune cells, leading to tissue damage. Currently available in vitro models mainly recapitulate the viral life cycle but fail to model immune cell-mediated pathogenesis. Here we build macrophage-augmented organoids (MaugOs) by integrating macrophages into primary organoids that are cultured from human liver tissues. We test the infections of two RNA viruses, hepatitis E virus and SARS-CoV-2, and one DNA virus, monkeypox virus, which either primarily or secondarily affect the human liver. In all three models of acute viral diseases, MaugOs recapitulate infection and the resulting inflammatory response, although to different levels. We use this system to dissect the multifunctional role of human bile on hepatitis E virus replication and the inflammatory response through distinct mechanisms of action. We also show that MaugOs recapitulate features of inflammatory cell death triggered by hepatitis E virus infection when integrated with pro-inflammatory macrophages. Furthermore, we demonstrate a proof of concept in MaugOs for development of multitarget therapeutics that simultaneously target the virus, inflammatory response and the resultant inflammatory cell death.
急性病毒性疾病的病理生理学很复杂。其特征是由免疫细胞驱动的强烈炎症反应，导致组织损伤。目前可用的体外模型主要重现病毒生命周期，但无法模拟免疫细胞介导的发病机制。在这里，我们通过将巨噬细胞整合到从人类肝脏组织培养的原代类器官中，构建了巨噬细胞增强类器官（MaugOs）。我们测试了两种RNA病毒，即戊型肝炎病毒和严重急性呼吸综合征冠状病毒2（SARS-CoV-2），以及一种DNA病毒，即猴痘病毒的感染情况，这些病毒要么主要要么次要影响人类肝脏。在所有三种急性病毒性疾病模型中，MaugOs都能重现感染及由此产生的炎症反应，尽管程度不同。我们利用这个系统通过不同的作用机制剖析了人胆汁对戊型肝炎病毒复制和炎症反应的多功能作用。我们还表明，当与促炎性巨噬细胞整合时，MaugOs能重现戊型肝炎病毒感染引发的炎性细胞死亡特征。此外，我们在MaugOs中展示了开发同时靶向病毒、炎症反应及由此产生的炎性细胞死亡的多靶点疗法的概念验证。
