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| Item Type: | Article |
|---|---|
| Title: | Epithelial response to IFN-γ promotes SARS-CoV-2 infection |
| Creators Name: | Heuberger, J. and Trimpert, J. and Vladimirova, D. and Goosmann, C. and Lin, M. and Schmuck, R. and Mollenkopf, H.J. and Brinkmann, V. and Tacke, F. and Osterrieder, N. and Sigal, M. |
| Abstract: | SARS-CoV-2, the agent that causes COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN-γ, which is elevated in COVID-19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS-CoV-2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS-CoV-2 infection and resulted in enhanced virus production in infected cells. Similarly, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN-γ-driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS-CoV-2, which may have an impact on disease outcome and virus transmission. |
| Keywords: | SARS-CoV-2, Organoids, Interferon, Differentiation, ACE2, Animals, Mice |
| Source: | EMBO Molecular Medicine |
| ISSN: | 1757-4676 |
| Publisher: | EMBO Press / Wiley |
| Volume: | 13 |
| Number: | 4 |
| Page Range: | e13191 |
| Date: | 9 April 2021 |
| Official Publication: | https://doi.org/10.15252/emmm.202013191 |
| PubMed: | View item in PubMed |
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