Macrophage-augmented organoids recapitulate the complex pathophysiology of viral diseases and enable development of multitarget therapeutics
Abstract
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.
Authors 24
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Erasmus MC · Southern University of Science and Technology
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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Fundació Lluita contra les Infeccions
Affiliation as printed
Sexually Transmitted Infections and Skin Neglected Tropical Diseases Section, Fight Infectious Diseases Foundation, Hospital Germans Trias i Pujol, Badalona, Spain
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Southern University of Science and Technology
Affiliation as printed
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Affiliation as printed
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, the Netherlands
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Erasmus MC · Southern University of Science and Technology
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Queen Mary University of London · Blizard Institute
Affiliation as printed
Blizard Institute and SHARE Collaborative, Department of Infection and Immunity, Queen Mary University of London, London, UK
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University of Toronto · Toronto General Hospital · Erasmus MC
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Toronto Center for Liver Disease, Toronto General Hospital, University of Toronto, Canada
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Affiliation as printed
Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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Luc J. W. van der Laan corresponding
Erasmus MC · Erasmus MC Transplant Institute
Affiliation as printed
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, the Netherlands
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Qiuwei Pan corresponding
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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