SARS-CoV-2 utilizes the ACE2 transmembrane peptidase as essential cellular entry receptor. Several studies have suggested abundant ACE2 expression in the human lung, inferring strong permissiveness to SARS-CoV-2 infection with resultant alveolar damage and lung injury. Against this expectation, we provide evidence that ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation in the human alveolus. Instead, spectral imaging of ex vivo infected human lungs and COVID-19 autopsy samples depicted that alveolar macrophages were frequently positive for SARS-CoV-2, indicating viral phagocytosis. Single-cell transcriptomics of SARS-CoV-2 infected human lung tissue further revealed strong inflammatory and anti-viral activation responses in macrophages and monocytes, comparable to those induced by MERS-CoV, but with virus-specific gene expression profiles. Collectively, our findings indicate that severe lung injury in COVID-19 likely results from an overwhelming immune activation rather than direct viral damage of the alveolar compartment.
Funding: ACH, LES, SH were supported by Berlin University Alliance GC2 Global Health (Corona Virus Pre-Exploration Project). ACH, SH, TW and CD were supported by BMBF (RAPID) and ACH, SH by BMBF (alvBarriereCOVID-19). KH, LB, SL, SH, CD, TW, ACH were funded by BMBF (NFN-COVID 19, Organo-Strat). KH, NS, LES, MW, SH, ADG, CD, TW and ACH were supported by DFG (SFB-TR 84). ACH was supported by BIH, Charite 3R, and Charité-Zeiss MultiDim. KH was supported by BMBF (Camo-COVID-19). MW, NS and SH was supported by BMBF (PROVID). MW and NS was supported by BIH and BMBF (SYMPATH, CAPSyS, NAPKON). BO and DB were funded through the BIH Clinical Single Cell Bioinformatics Pipeline. LB was supported by the BMBF (CoIMMUNE), the DFG (KFO 342) and the IZKF of the Medical Faculty of the WWU.
Conflict of Interest: The authors declare no competing interests.
Ethical Approval: The study was approved by the ethics committee at the Charité clinic (projects EA2/079/13) and Ärztekammer Westfalen-Lippe and of the Westfälischen Wilhelms-Universität (AZ: 2016-265-f-S). Written informed consent was obtained from all patients.
Keywords: SARS-CoV-2, Covid-19, human lung, pneumonia, ARDS, alveolar macrophages, monocytes, immune activation, influenza, MERS-CoV, SARS-CoV, alveolar type II cells, autopsy, ACE2, TMPRSS2, permissiveness, lung damage, lung injury, alveolar damage, immunopathogenesis
Hönzke, Katja and Obermayer, Benedikt and Mache, Christin and Fatykhova, Diana and Kessler, Mirjana and Dökel, Simon and Wyler, Emanuel and Hoffmann, Karen and Schulze, Jessica and Mieth, Maren and Hellwig, Katharina and Biere, Barbara and Brunotte, Linda and Mecate-Zambrano, Angeles and Hoppe, Judith and Dohmen, Melanie and Hinze, Christian and Elezkurtaj, Sefer and Tönnies, Mario and Bauer, Torsten and Eggeling, Stephan and Tran, Hong-Linh and Schneider, Paul and Neudecker, Jens and Rückert, Jens-Carsten and Schmidt-Ott, Kai and Busch, Jonas and Klauschen, Frederick and Horst, David and Radbruch, Helena and Heppner, Frank and Corman, Victor M. and Niemeyer, Daniela and Müller, Marcel Alexander and Goffinet, Christine and Beule, Dieter and Landthaler, Markus and Ludwig, Stephan and Niedobitek, Gerald and Suttorp, Norbert and Witzenrath, Martin and Gruber, Achim and Drosten, Christian and Sander, Leif E. and Wolff, Thorsten and Hippenstiel, Stefan and Hocke, Andreas C., Human Lungs Show Limited Permissiveness for SARS-CoV-2 Due to Scarce ACE2 Levels But Strong Virus-Induced Immune Activation in Alveolar Macrophages. Available at SSRN: https://ssrn.com/abstract=3687020 or http://dx.doi.org/10.2139/ssrn.3687020
This version of the paper has not been formally peer reviewed.
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