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Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages

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. and Obermayer, B. and Mache, C. and Fathykova, D. and Kessler, M. and Dökel, S. and Wyler, E. and Baumgardt, M. and Löwa, A. and Hoffmann, K. and Graff, P. and Schulze, J. and Mieth, M. and Hellwig, K. and Demir, Z. and Biere, B. and Brunotte, L. and Mecate-Zambrano, A. and Bushe, J. and Dohmen, M. and Hinze, C. and Elezkurtaj, S. and Tönnies, M. and Bauer, T.T. and Eggeling, S. and Tran, H.L. and Schneider, P. and Neudecker, J. and Rückert, J.C. and Schmidt-Ott, K.M. and Busch, J. and Klauschen, F. and Horst, D. and Radbruch, H. and Radke, J. and Heppner, F. and Corman, V.M. and Niemeyer, D. and Müller, M.A. and Goffinet, C. and Mothes, R. and Pascual-Reguant, A. and Hauser, A.E. and Beule, D. and Landthaler, M. and Ludwig, S. and Suttorp, N. and Witzenrath, M. and Gruber, A.D. and Drosten, C. and Sander, L.E. and Wolff, T. and 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.
Source:European Respiratory Journal
ISSN:0903-1936
Publisher:European Respiratory Society
Date:21 June 2022
Official Publication:https://doi.org/10.1183/13993003.02725-2021
PubMed:View item in PubMed

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