SARS-CoV-2 infection and replication in human fetal and pediatric gastric organoids
SARS-CoV-2 infection and replication in human fetal and pediatric gastric organoids
Abstract Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as a respiratory illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This is particularly true in children in whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. By contrast, fetuses seem to be rarely affected by COVID-19, although the virus has been detected in placentas of affected women. These observations raise the question of whether the virus can infect and replicate within the stomach once ingested. Moreover, it is not yet clear whether active replication of SARS-CoV-2 is possible in the stomach of children or in fetuses at different developmental stages. Here we show the novel derivation of fetal gastric organoids from 8-21 post-conception week (PCW) fetuses, and from pediatric biopsies, to be used as an in vitro model for SARS-CoV-2 gastric infection. Gastric organoids recapitulate human stomach with linear increase of gastric mucin 5AC along developmental stages, and expression of gastric markers pepsinogen, somatostatin, gastrin and chromogranin A. In order to investigate SARS-CoV-2 infection with minimal perturbation and under steady-state conditions, we induced a reversed polarity in the gastric organoids (RP-GOs) in suspension. In this condition of exposed apical polarity, the virus can easily access viral receptor angiotensin-converting enzyme 2 (ACE2). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, where viral nucleoprotein is expressed in cells undergoing programmed cell death, while the efficiency of infection is significantly lower in fetal organoids. The RP-GOs derived from pediatric patients show sustained robust viral replication of SARS-CoV-2, compared with organoids derived from fetal stomachs. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we established the first expandable human gastric organoid culture across fetal developmental stages, and we support the hypothesis that fetal tissue seems to be less susceptible to SARS-CoV-2 infection, especially in early stages of development. However, the virus can efficiently infect gastric epithelium in pediatric patients, suggesting that the stomach might have an active role in fecal-oral transmission of SARS-CoV-2.
Cacchiarelli Davide、Mazzetto Eva、Manfredi Anna、Colantuono Chiara、Li Vivian Sze Wing、Eaton Simon、Giobbe Giovanni Giuseppe、Gagliano Onelia、Laterza Cecilia、Pagliari Matteo、Pellegata Alessandro、Luni Camilla、Jones Brendan C.、Thapar Nikhil、Bortolami Alessio、Bonfante Francesco、De Coppi Paolo、Di Filippo Lucio、Elvassore Nicola、Zambaiti Elisa、Perin Silvia、Stuart Hannah T.
Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics||Department of Translational Medicine, University of Naples Federico IILab. of Experimental Animal Models, Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle VenezieTelethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative GenomicsTelethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative GenomicsStem Cell and Cancer Biology Lab, the Francis Crick InstituteStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College LondonStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College LondonVeneto Institute of Molecular Medicine (VIMM)Veneto Institute of Molecular Medicine (VIMM)Lab. of Experimental Animal Models, Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle VenezieStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College LondonShanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech UniversityStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College LondonStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College London||Gastroenterology, Hepatology and Liver Transplant, Queensland Children?ˉs HospitalLab. of Experimental Animal Models, Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle VenezieLab. of Experimental Animal Models, Division of Comparative Biomedical Sciences, Istituto Zooprofilattico Sperimentale delle VenezieStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College London||Dept. of Specialist Neonatal and Paediatric Surgery, Great Ormond Street HospitalNext Generation Diagnostic srlStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College London||Veneto Institute of Molecular Medicine (VIMM)||Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University||Dept. of Industrial Engineering, University of PadovaStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College London||Veneto Institute of Molecular Medicine (VIMM)||Dept. Women?ˉs and Children?ˉs Health, University of PadovaStem Cell and Regenerative Medicine Section, GOS Institute of Child Health, University College LondonVeneto Institute of Molecular Medicine (VIMM)
医学研究方法基础医学分子生物学
Cacchiarelli Davide,Mazzetto Eva,Manfredi Anna,Colantuono Chiara,Li Vivian Sze Wing,Eaton Simon,Giobbe Giovanni Giuseppe,Gagliano Onelia,Laterza Cecilia,Pagliari Matteo,Pellegata Alessandro,Luni Camilla,Jones Brendan C.,Thapar Nikhil,Bortolami Alessio,Bonfante Francesco,De Coppi Paolo,Di Filippo Lucio,Elvassore Nicola,Zambaiti Elisa,Perin Silvia,Stuart Hannah T..SARS-CoV-2 infection and replication in human fetal and pediatric gastric organoids[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2020.06.24.167049.点此复制
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