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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Jens-C. Rückert reports support from DFG RA 2491/1-1, BMBF (Defeat Pandemics).
Conflict of interest: Helena Radbruch reports support from DFG RA 2491/1-1, BMBF (Defeat Pandemics).
Conflict of interest: Anja Hauser reports support from Charité – Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin.
Conflict of interest: Thorsten Wolff reports support from Federal Ministry of Education and Research (BMBF) grant 01K12006F.
Conflict of interest: Mirjana Kessler reports grants from BMBF Organo-Strat, Einstein 3R.
Conflict of interest: Melanie Dohmen reports contract with Max-Delbrück Center, Berlin; grant from Gender Equality Fund, Berlin Institute of Health.
Conflict of interest: Frederick Klauschen reports consulting fees, lecture honoraria, travel support and participation on advisory boards with BMS, Novartis, Roche, Lilly. Frederick Klauschen is a Co-Founder of AI-BIH/Charité-Spinoff Aignostics GmbH.
Conflict of interest: Frank Heppner reports consulting fees, lecture honoraria, payment for expert testimony and leadership role at Novartis, AstraZence, ThinkHealth Hygiene Solutions.
Conflict of interest: Victor Corman reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor).
Conflict of interest: Daniela Niemeyer reports that Technische Universität Berlin, Freie Universität Berlin and Charité - Universitätsmedizin have filed a patent application for siRNAs inhibiting SARS-CoV-2 replication with DN as coauthor.
Conflict of interest: Marcel A. Müller reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor); and has participated on an advisory board for ECDC/WHO.
Conflict of interest: Anja Hauser reports grants from Deutsche Forschungsgemeinschaft (HA5354/10-1, TRR130,P17 and C01, HA5354/8-1).
Conflict of interest: Stephan Ludwig reports consulting fees from Atriva Therapeutics GmbH, Biontec se; and has patent PCT/EP2021/063485 pending.
Conflict of interest: Martin Witzenrath reports grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Quark Pharma, Takeda Pharma, Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim; consulting fees from Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Aptarion, Glaxo Smith Kline, Sinoxa, Biotest; lecture honoraria from Astra Zeneca, Berlin Chemie, Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, Glaxo Smith Kline, Biotest, Bayer Health Care; and has the following patents issued: EPO 12181535.1 : IL-27 for modulation of immune response in acute lung injury, WO/2010/094491: Means for inhibiting the expression of Ang-2, DE 102020116249.9 : Camostat/ Niclosamide cotreatment in SARS-CoV-2 infected human lung cells.
Conflict of interest: All other authors have nothing to disclose.
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- Received October 15, 2021.
- Accepted May 25, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
