Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.
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Hönzke Katja, Obermayer Benedikt, Mache Christin, Fatykhova Diana, Kessler Mirjana, Dökel Simon, 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, 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, Drosten Christian, Sander Leif-Erik, Wolff Thorsten, Hippenstiel Stefan, Hocke Andreas C
Аннотация
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.