Publikationsdatenbank

Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages (2022)

Art

Poster

Autoren

Hönzke, Katja

Obermayer, Benedikt

Mache, Christin

Fathykova, Diana

Kessler, Mirjana

Dökel, Simon (WE 12)

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 (WE 12)

Dohmen, Melanie

Hinze, Christian

Elezkurtaj, Sefer

Tönnies, Mario

Bauer, Torsten T.

Eggeling, Stephan

Tran, Hong-Linh

Schneider, Paul

Neudecker, Jens

Rückert, Jens C.

Schmidt-Ott, Kai M.

Busch, Jonas

Klauschen, Frederick

Horst, David

Radbruch, Helena

Radke, Josefine

Heppner, Frank

Corman, Victor M.

Niemeyer, Daniela

Müller, 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. (WE 12)

Drosten, Christian

Sander, Leif-Erik

Wolff, Thorsten

Hippenstiel, Stefan

Hocke, Andreas C.

Kongress

3. Internationale Konferenz des SFB-TR 84 : innate immunity of the lung – improving pneumonia outcome

Berlin, 08. – 10.09.2022

Quelle

The European respiratory journal

Bandzählung: 60

Heftzählung: 6

Seiten: Artikel 2102725

ISSN: 0903-1936

Sprache

Englisch

Verweise

URL (Volltext): https://erj.ersjournals.com/content/60/6/2102725

DOI: 10.1183/13993003.02725-2021

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.