Macrophage-augmented organoids recapitulate the complex pathophysiology of viral diseases and enable development of multitarget therapeutics

Abstract The pathophysiology of viral diseases is complex, and often evokes strong inflammatory responses and tissue damage. Currently available in vitro models mainly recapitulate the viral life cycle per se , but fail to model immune cell-mediated pathogenesis. Here we build macrophage-augmented organoids (MaugOs) by integrating macrophages into organoids that are cultured from human liver tissues. We test the infections of two RNA viruses—hepatitis E virus (HEV) and SARS-CoV-2, and one DNA virus—monkeypox virus (MPXV), which either primarily or secondarily affect the human liver. In all three viral disease modalities, MaugOs recapitulate both infection and the resulting inflammatory response, albert to different levels. Intriguingly, this system showcases the ability to dissect the multifunctional role of human bile on HEV replication and inflammatory response through distinct mechanisms of action. MaugOs especially when integrated with pro-inflammatory macrophages recapitulate a prominent feature of inflammatory cell death triggered by HEV infection. Furthermore, we demonstrate a proof-of-concept in MaugOs to develop multitarget therapeutic strategies that simultaneously target the virus, inflammatory response, and the resultant inflammatory cell death.