Macrophage-augmented intestinal organoids model virus-host interactions in enteric viral diseases and facilitate therapeutic development
Nature Communications, vol. 16, pp. 4475
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.
Authors 19
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Sichuan University · Erasmus MC · West China Hospital of Sichuan University · Shandong Agricultural University
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, 271018, China
Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu, 610041, 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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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 Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, China
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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 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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Shandong Agricultural University
Affiliation as printed
Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, 271018, 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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Norwegian University of Science and Technology
Affiliation as printed
Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7028, Trondheim, Norway
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University Health Network · Toronto General Hospital · Erasmus MC
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, Canada
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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 Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, China
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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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Pengfei Li corresponding
Sichuan University · Erasmus MC · West China Hospital of Sichuan University
Affiliation as printed
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. p.li@erasmusmc.nl
Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu, 610041, China. p.li@erasmusmc.nl
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