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Hönzke, Katja; Obermayer, Benedikt; Mache, Christin; Fatykhova, Diana; Kessler, Mirjana; Dökel, Simon; Wyler, Emanuel; Baumgardt, Morris; Löwa, Anna; Hoffmann, Karen; Graff, Patrick; Schulze, Jessica; Mieth, Maren; Hellwig, Katharina; Demir, Zeynep; Biere, Barbara; Brunotte, Linda; Mecate-Zambrano, Angeles; Bushe, Judith; Dohmen, Melanie; Hinze, Christian; Elezkurtaj, Sefer; Tönnies, Mario; Bauer, Torsten T.; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages
  • Beteiligte: Hönzke, Katja; Obermayer, Benedikt; Mache, Christin; Fatykhova, Diana; Kessler, Mirjana; Dökel, Simon; Wyler, Emanuel; Baumgardt, Morris; Löwa, Anna; Hoffmann, Karen; Graff, Patrick; Schulze, Jessica; Mieth, Maren; Hellwig, Katharina; Demir, Zeynep; Biere, Barbara; Brunotte, Linda; Mecate-Zambrano, Angeles; Bushe, Judith; Dohmen, Melanie; Hinze, Christian; Elezkurtaj, Sefer; Tönnies, Mario; Bauer, Torsten T.; [...]
  • Erschienen: European Respiratory Society (ERS), 2022
  • Erschienen in: European Respiratory Journal
  • Sprache: Englisch
  • DOI: 10.1183/13993003.02725-2021
  • ISSN: 0903-1936; 1399-3003
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 “gain-of-function” experiments were applied to 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 Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate<jats:italic>ex vivo</jats:italic>results.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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,<jats:italic>ex vivo</jats:italic>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 nonproductive 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.</jats:p></jats:sec>