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Human Lungs Show Limited Permissiveness for SARS-CoV-2 Due to Scarce ACE2 Levels But Strong Virus-Induced Immune Activation in Alveolar Macrophages

73 Pages Posted: 6 Oct 2020 Publication Status: Review Complete

See all articles by Katja Hönzke

Katja Hönzke

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Benedikt Obermayer

Charité - Universitätsmedizin Berlin

Christin Mache

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses”

Diana Fatykhova

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Mirjana Kessler

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Simon Dökel

Free University of Berlin (FUB) - Institut für Tierpathologie

Emanuel Wyler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Karen Hoffmann

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Jessica Schulze

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses”

Maren Mieth

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Katharina Hellwig

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Barbara Biere

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses”

Linda Brunotte

Westfaelische Wilhelms Universität - Institute of Virology

Angeles Mecate-Zambrano

Westfaelische Wilhelms Universität - Institute of Virology

Judith Hoppe

Free University of Berlin (FUB) - Department of Veterinary Pathology

Melanie Dohmen

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Christian Hinze

Charité - Universitätsmedizin Berlin - Department of Nephrology

Sefer Elezkurtaj

Charité - Universitätsmedizin Berlin - Department of Pathology

Mario Tönnies

Chest Hospital Heckeshorn - HELIOS Clinic Emil von Behring

Torsten Bauer

Chest Hospital Heckeshorn - HELIOS Clinic Emil von Behring

Stephan Eggeling

Vivantes Clinics Neukölln - Department of Thoracic Surgery

Hong-Linh Tran

Vivantes Clinics Neukölln - Department of Thoracic Surgery

Paul Schneider

DRK Clinics - Department for Thoracic Surgery

Jens Neudecker

Charité - Universitätsmedizin Berlin - Department of General, Visceral, Vascular and Thoracic Surgery

Jens-Carsten Rückert

Charité - Universitätsmedizin Berlin - Department of General, Visceral, Vascular and Thoracic Surgery

Kai Schmidt-Ott

Charité - Universitätsmedizin Berlin - Department of Nephrology and Medical Intensive Care

Jonas Busch

Charité - Universitätsmedizin Berlin - Clinic for Urology

Frederick Klauschen

Charité - Universitätsmedizin Berlin - Department of Pathology

David Horst

Charité - Universitätsmedizin Berlin - Department of Pathology

Helena Radbruch

Charité - Universitätsmedizin Berlin - Institute for Neuropathology

Frank Heppner

Charité - Universitätsmedizin Berlin - Institute for Neuropathology

Victor M. Corman

Charité - Universitätsmedizin Berlin - Institute of Virology

Daniela Niemeyer

Charité - Universitätsmedizin Berlin

Marcel Alexander Müller

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin

Christine Goffinet

Charité - Universitätsmedizin Berlin - Institute of Virology

Dieter Beule

Charité - Universitätsmedizin Berlin

Markus Landthaler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Stephan Ludwig

Westfaelische Wilhelms Universität - Institute of Virology

Gerald Niedobitek

Unfallkrankenhaus Berlin - Institute of Pathology

Norbert Suttorp

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Martin Witzenrath

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Achim Gruber

Free University of Berlin (FUB) - Institut für Tierpathologie

Christian Drosten

Charité - Universitätsmedizin Berlin - Institute of Virology

Leif E. Sander

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Thorsten Wolff

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses”

Stefan Hippenstiel

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Andreas C. Hocke

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

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Abstract

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

Suggested Citation

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.

Katja Hönzke

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

Berlin
Germany

Benedikt Obermayer

Charité - Universitätsmedizin Berlin ( email )

Charitéplatz 1
Berlin, 10117
Germany

Christin Mache

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses” ( email )

Berlin
Germany

Diana Fatykhova

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Charitéplatz 1
Berlin, 10117
Germany

Mirjana Kessler

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Charitéplatz 1
Berlin, 10117
Germany

Simon Dökel

Free University of Berlin (FUB) - Institut für Tierpathologie ( email )

Van't-Hoff-Str. 8
Berlin, Berlin 14195
Germany

Emanuel Wyler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Anna-Louisa-Karsch-Straße 2
Robert-Rössle-Str. 10
Berlin, Berlin 10178
United States

Karen Hoffmann

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Jessica Schulze

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses” ( email )

Berlin
Germany

Maren Mieth

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Charitéplatz 1
Berlin, 10117
Germany

Katharina Hellwig

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Charitéplatz 1
Berlin, 10117
Germany

Barbara Biere

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses” ( email )

Berlin
Germany

Linda Brunotte

Westfaelische Wilhelms Universität - Institute of Virology ( email )

Angeles Mecate-Zambrano

Westfaelische Wilhelms Universität - Institute of Virology ( email )

Judith Hoppe

Free University of Berlin (FUB) - Department of Veterinary Pathology ( email )

Van't-Hoff-Str. 8
Berlin, Berlin 14195
Germany

Melanie Dohmen

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Charitéplatz 1
Berlin, 10117
Germany

Christian Hinze

Charité - Universitätsmedizin Berlin - Department of Nephrology

Charitéplatz 1
Berlin, 10117
Germany

Sefer Elezkurtaj

Charité - Universitätsmedizin Berlin - Department of Pathology

Charitéplatz 1
Berlin, 10117
Germany

Mario Tönnies

Chest Hospital Heckeshorn - HELIOS Clinic Emil von Behring ( email )

Torsten Bauer

Chest Hospital Heckeshorn - HELIOS Clinic Emil von Behring ( email )

Stephan Eggeling

Vivantes Clinics Neukölln - Department of Thoracic Surgery ( email )

Hong-Linh Tran

Vivantes Clinics Neukölln - Department of Thoracic Surgery ( email )

Paul Schneider

DRK Clinics - Department for Thoracic Surgery

Jens Neudecker

Charité - Universitätsmedizin Berlin - Department of General, Visceral, Vascular and Thoracic Surgery

Charitéplatz 1
Berlin, 10117
Germany

Jens-Carsten Rückert

Charité - Universitätsmedizin Berlin - Department of General, Visceral, Vascular and Thoracic Surgery

Charitéplatz 1
Berlin, 10117
Germany

Kai Schmidt-Ott

Charité - Universitätsmedizin Berlin - Department of Nephrology and Medical Intensive Care

Charitéplatz 1
Berlin, 10117
Germany

Jonas Busch

Charité - Universitätsmedizin Berlin - Clinic for Urology

Charitéplatz 1
Berlin, 10117
Germany

Frederick Klauschen

Charité - Universitätsmedizin Berlin - Department of Pathology

Charitéplatz 1
Berlin, 10117
Germany

David Horst

Charité - Universitätsmedizin Berlin - Department of Pathology

Germany

Helena Radbruch

Charité - Universitätsmedizin Berlin - Institute for Neuropathology

Charitéplatz 1
Berlin, 10117
Germany

Frank Heppner

Charité - Universitätsmedizin Berlin - Institute for Neuropathology

Charitéplatz 1
Berlin, 10117
Germany

Victor M. Corman

Charité - Universitätsmedizin Berlin - Institute of Virology ( email )

Charitéplatz 1
Berlin, 10117
Germany

Daniela Niemeyer

Charité - Universitätsmedizin Berlin

Marcel Alexander Müller

Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin ( email )

Christine Goffinet

Charité - Universitätsmedizin Berlin - Institute of Virology

Dieter Beule

Charité - Universitätsmedizin Berlin

Charitéplatz 1
Berlin, 10117
Germany

Markus Landthaler

Helmholtz Association of German Research Centres - Berlin Institute for Medical Systems Biology

Anna-Louisa-Karsch-Straße 2
Robert-Rössle-Str. 10
Berlin, Berlin 10178
United States

Stephan Ludwig

Westfaelische Wilhelms Universität - Institute of Virology

Gerald Niedobitek

Unfallkrankenhaus Berlin - Institute of Pathology ( email )

Norbert Suttorp

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine

Martin Witzenrath

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

Achim Gruber

Free University of Berlin (FUB) - Institut für Tierpathologie ( email )

Van't-Hoff-Str. 8
Berlin, Berlin 14195
Germany

Christian Drosten

Charité - Universitätsmedizin Berlin - Institute of Virology ( email )

Berlin
Germany

Leif E. Sander

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

Thorsten Wolff

Robert Koch Institute - Unit 17 “Influenza and other Respiratory Viruses” ( email )

Berlin
Germany

Stefan Hippenstiel

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

Berlin
Germany

Andreas C. Hocke (Contact Author)

Charité - Universitätsmedizin Berlin - Department of Infectious Diseases and Respiratory Medicine ( email )

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