SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response
| Autor: | Konstantinos-Dionysios Alysandratos, Eric J. Burks, Mary Lou Beermann, Ellen L Suder, Ruobing Wang, Esther Bullitt, Jessie Huang, Kristine M. Abo, Judith Olejnik, Chantelle Simone-Roach, Arjun Sharma, Elke Mühlberger, Adam J. Hume, Mohsan Saeed, Rhiannon B. Werder, Markus Bosmann, Jonathan Lindstrom-Vautrin, Darrell N. Kotton, Anne Hinds, Carlos Villacorta-Martin, Andrew A. Wilson, Finn Hawkins |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cell
Virus Replication Pathogenesis 0302 clinical medicine Interferon RNA-Seq Enzyme Inhibitors Induced pluripotent stem cell Cells Cultured 0303 health sciences Alanine Serine Endopeptidases respiratory system Cell biology medicine.anatomical_structure Molecular Medicine medicine.symptom medicine.drug Pluripotent Stem Cells Resource Alveolar Epithelium iPSCs Inflammation Biology Antiviral Agents Models Biological Article lung Alveolar cells 03 medical and health sciences Downregulation and upregulation Drug Development Genetics medicine Animals Humans Secretion Progenitor cell alveolar epithelial cell 030304 developmental biology Lung SARS-CoV-2 alveolar type 2 cell COVID-19 Cell Biology Epithelium Adenosine Monophosphate respiratory tract diseases human induced pluripotent stem cells inflammation Alveolar Epithelial Cells Immunology 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell bioRxiv |
| ISSN: | 1875-9777 1934-5909 |
| Popis: | A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development. Graphical Abstract Highlights • iPSC-derived alveolar type 2 cells (iAT2s) are permissive to SARS-CoV-2 infection • SARS-CoV-2 induces an iAT2-intrinsic cytotoxicity and inflammatory response • iAT2s effectively model antiviral drug response and may be used for further drug development Huang et al. show that human iPSC-derived alveolar type 2 cells (iAT2s) can be used to model COVID-19. They find that iAT2s in air-liquid interface culture are permissive to SARS-CoV-2 infection and show that SARS-CoV-2 induces a rapid inflammatory phenotype predominated by NF-κB signaling. |
| Databáze: | OpenAIRE |
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