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


  • 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


  • European Respiratory Journal


  • Eur Respir J 60 (6): 2102725


  • 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.