The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Current...The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines(transformed or cancer cells)and species differences between animals and humans.Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs.Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells(hESCs)-derived lung organoids,including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs.The infected ceils were ciliated,club,and alveolar type 2(AT2)cells,which were sequentially located from the proximal to the distal airway and terminal alveoli,respectively.Additionally,RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes,especially lipid metabolism,in addition to the well-known upregulation of immune response.Further,Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids.Therefore,human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.展开更多
基金This work was supported by grants from National Natural Science Foundation of China(Grant Nos.82070002,82072329,81872511,and 81670093)Frontier Research Program of Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory)(2018GZR110105005)+6 种基金National Science and Technology Major Project(2018ZX10301101)the Natural Science Foundation of Guangdong Province(2018A030313455)the Program of Department of Science and Technology of Guangdong Province(2014B020212018)National Key Research and Development Project(2018YFA0507201)the special project for COVID-19 of Guangzhou Regenerative Medicine and Health Guangdong Labo・ratory(2020GZR110106006)the emergency grants for prevention and control of SARS-CoV-2 of Guangdong province(2020B111108001)National Postdoctoral Program for Innovative Talent(BX20190089).
文摘The coronavirus disease 2019(COVID-19)pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is spread primary via respiratory droplets and infects the lungs.Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines(transformed or cancer cells)and species differences between animals and humans.Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs.Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells(hESCs)-derived lung organoids,including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs.The infected ceils were ciliated,club,and alveolar type 2(AT2)cells,which were sequentially located from the proximal to the distal airway and terminal alveoli,respectively.Additionally,RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes,especially lipid metabolism,in addition to the well-known upregulation of immune response.Further,Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids.Therefore,human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.
