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

Hoenzke, Katja; Obermayer, Benedikt; Mache, Christin; Fathykova, Diana; Kessler, Mirjana; Doekel, Simon; Wyler, Emanuel; Baumgardt, Morris; Loewa, 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; Toennies, Mario; Bauer, Torsten T.; Eggeling, Stephan; Hong-Linh, Tran; Schneider, Paul; Neudecker, Jens; Rueckert, Jens C.; Schmidt-Ott, Kai M.; Busch, Jonas; Klauschen, Frederick; Horst, David; Radbruch, Helena; Radke, Josefine; Heppner, Frank; Corman, Victor M.; Niemeyer, Daniela; Mueller, Marcel A.; Goffinet, Christine; Mothes, Ronja; Pascual-Reguant, Anna; Hauser, Anja Erika; Beule, Dieter; Landthaler, Markus; Ludwig, Stephan; Suttorp, Norbert; Witzenrath, Martin; Gruber, Achim D.; Drosten, Christian; Sander, Leif-Erik; Wolff, Thorsten; Hippenstiel, Stefan und Hocke, Andreas C. (2022): Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages. In: European Respiratory Journal, Bd. 60, Nr. 6, 2102725

Abstract

Background 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.Methods 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 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 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.Conclusions 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0903-1936
• Sprache: Englisch