Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages
Authors
- K. Hönzke
- B. Obermayer
- C. Mache
- D. Fathykova
- M. Kessler
- S. Dökel
- E. Wyler
- M. Baumgardt
- A. Löwa
- K. Hoffmann
- P. Graff
- J. Schulze
- M. Mieth
- K. Hellwig
- Z. Demir
- B. Biere
- L. Brunotte
- A. Mecate-Zambrano
- J. Bushe
- M. Dohmen
- C. Hinze
- S. Elezkurtaj
- M. Tönnies
- T.T. Bauer
- S. Eggeling
- H.L. Tran
- P. Schneider
- J. Neudecker
- J.C. Rückert
- K.M. Schmidt-Ott
- J. Busch
- F. Klauschen
- D. Horst
- H. Radbruch
- J. Radke
- F. Heppner
- V.M. Corman
- D. Niemeyer
- M.A. Müller
- C. Goffinet
- R. Mothes
- A. Pascual-Reguant
- A.E. Hauser
- D. Beule
- M. Landthaler
- S. Ludwig
- N. Suttorp
- M. Witzenrath
- A.D. Gruber
- C. Drosten
- L.E. Sander
- T. Wolff
- S. Hippenstiel
- A.C. Hocke
Journal
- European Respiratory Journal
Citation
- Eur Respir J 60 (6): 2102725
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.