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| Item Type: | Article |
|---|---|
| Title: | Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages |
| Creators Name: | Hönzke, K., Obermayer, B., Mache, C., Fathykova, D., Kessler, M., Dökel, S., Wyler, E., Baumgardt, M., Löwa, A., Hoffmann, K., Graff, P., Schulze, J., Mieth, M., Hellwig, K., Demir, Z., Biere, B., Brunotte, L., Mecate-Zambrano, A., Bushe, J., Dohmen, M., Hinze, C., Elezkurtaj, S., Tönnies, M., Bauer, T.T., Eggeling, S., Tran, H.L., Schneider, P., Neudecker, J., Rückert, J.C., Schmidt-Ott, K.M., Busch, J., Klauschen, F., Horst, D., Radbruch, H., Radke, J., Heppner, F., Corman, V.M., Niemeyer, D., Müller, M.A., Goffinet, C., Mothes, R., Pascual-Reguant, A., Hauser, A.E., Beule, D., Landthaler, M., Ludwig, S., Suttorp, N., Witzenrath, M., Gruber, A.D., Drosten, C., Sander, L.E., Wolff, T., Hippenstiel, S. and Hocke, A.C. |
| Abstract: | BACKGROUND: SARS-CoV-2 utilizes the ACE2 transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 'gain-of-function' experiments were applied on infected human lung explants and adult stem cell-derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and MERS-CoV. COVID-19 autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed non-productive virus uptake and a related inflammatory and anti-viral activation, especially in 'inflammatory alveolar macrophages', comparable to those induced by SARS-CoV and MERS-CoV but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 likely results from a macrophage triggered immune activation rather than direct viral damage of the alveolar compartment. |
| Keywords: | Angiotensin-Converting Enzyme 2, COVID-19, Human Influenza, Lung, Alveolar Macrophages, Peptidyl-Dipeptidase A, Permissiveness, SARS-CoV-2 |
| Source: | European Respiratory Journal |
| ISSN: | 0903-1936 |
| Publisher: | European Respiratory Society |
| Volume: | 60 |
| Number: | 6 |
| Page Range: | 2102725 |
| Date: | 1 December 2022 |
| Official Publication: | https://doi.org/10.1183/13993003.02725-2021 |
| PubMed: | View item in PubMed |
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