SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

Nils C. Gassen (), Jan Papies, Thomas Bajaj, Jackson Emanuel, Frederik Dethloff, Robert Lorenz Chua, Jakob Trimpert, Nicolas Heinemann, Christine Niemeyer, Friderike Weege, Katja Hönzke, Tom Aschman, Daniel E. Heinz, Katja Weckmann, Tim Ebert, Andreas Zellner, Martina Lennarz, Emanuel Wyler, Simon Schroeder, Anja Richter, Daniela Niemeyer, Karen Hoffmann, Thomas F. Meyer, Frank L. Heppner, Victor M. Corman, Markus Landthaler, Andreas C. Hocke, Markus Morkel, Nikolaus Osterrieder, Christian Conrad, Roland Eils, Helena Radbruch, Patrick Giavalisco, Christian Drosten and Marcel A. Müller ()
Additional contact information
Nils C. Gassen: University of Bonn, Medical Faculty
Jan Papies: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Thomas Bajaj: University of Bonn, Medical Faculty
Jackson Emanuel: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Frederik Dethloff: Max Planck Institute for Biology of Ageing
Robert Lorenz Chua: Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Jakob Trimpert: Institute of Virology, Freie Universität Berlin
Nicolas Heinemann: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Christine Niemeyer: University of Bonn, Medical Faculty
Friderike Weege: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Katja Hönzke: Molecular Imaging of Immunoregulation, Medizinische Klinik m.S. Infektiologie & Pneumologie, Charité-Universitätsmedizin Berlin
Tom Aschman: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Daniel E. Heinz: University of Bonn, Medical Faculty
Katja Weckmann: University of Bonn, Medical Faculty
Tim Ebert: University of Bonn, Medical Faculty
Andreas Zellner: University of Bonn, Medical Faculty
Martina Lennarz: University of Bonn, Medical Faculty
Emanuel Wyler: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Simon Schroeder: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Anja Richter: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Daniela Niemeyer: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Karen Hoffmann: Molecular Imaging of Immunoregulation, Medizinische Klinik m.S. Infektiologie & Pneumologie, Charité-Universitätsmedizin Berlin
Thomas F. Meyer: Institute of Clinical Molecular Biology, UKSH, Christian Albrechts University of Kiel
Frank L. Heppner: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Victor M. Corman: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Markus Landthaler: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Andreas C. Hocke: Molecular Imaging of Immunoregulation, Medizinische Klinik m.S. Infektiologie & Pneumologie, Charité-Universitätsmedizin Berlin
Markus Morkel: Institute for Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Nikolaus Osterrieder: Institute of Virology, Freie Universität Berlin
Christian Conrad: Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Roland Eils: Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Helena Radbruch: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Patrick Giavalisco: Max Planck Institute for Biology of Ageing
Christian Drosten: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Marcel A. Müller: Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.

Date: 2021
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DOI: 10.1038/s41467-021-24007-w

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