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SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals.
Gassen, Nils C; Papies, Jan; Bajaj, Thomas; Emanuel, Jackson; Dethloff, Frederik; Chua, Robert Lorenz; Trimpert, Jakob; Heinemann, Nicolas; Niemeyer, Christine; Weege, Friderike; Hönzke, Katja; Aschman, Tom; Heinz, Daniel E; Weckmann, Katja; Ebert, Tim; Zellner, Andreas; Lennarz, Martina; Wyler, Emanuel; Schroeder, Simon; Richter, Anja; Niemeyer, Daniela; Hoffmann, Karen; Meyer, Thomas F; Heppner, Frank L; Corman, Victor M; Landthaler, Markus; Hocke, Andreas C; Morkel, Markus; Osterrieder, Nikolaus; Conrad, Christian; Eils, Roland; Radbruch, Helena; Giavalisco, Patrick; Drosten, Christian; Müller, Marcel A.
  • Gassen NC; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany. nils.gassen@ukbonn.de.
  • Papies J; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Bajaj T; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Emanuel J; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Dethloff F; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Chua RL; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Trimpert J; Max Planck Institute for Biology of Ageing, Cologne, Germany.
  • Heinemann N; Center for Digital Health, Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Niemeyer C; Institute of Virology, Freie Universität Berlin, Berlin, Germany.
  • Weege F; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Hönzke K; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Aschman T; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Heinz DE; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Weckmann K; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Ebert T; Molecular Imaging of Immunoregulation, Medizinische Klinik m.S. Infektiologie & Pneumologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Zellner A; Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Lennarz M; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Wyler E; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Schroeder S; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Richter A; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Niemeyer D; Department of Psychiatry and Psychotherapy, University of Bonn, Medical Faculty, Bonn, Germany.
  • Hoffmann K; Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  • Meyer TF; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Heppner FL; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Corman VM; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Landthaler M; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Hocke AC; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Morkel M; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
  • Osterrieder N; Molecular Imaging of Immunoregulation, Medizinische Klinik m.S. Infektiologie & Pneumologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Conrad C; Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, UKSH, Christian Albrechts University of Kiel, Kiel, Germany.
  • Eils R; Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Radbruch H; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
  • Giavalisco P; Cluster of Excellence, NeuroCure, Berlin, Germany.
  • Drosten C; Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Müller MA; German Center for Infection Research (DZIF), partner site Charité, Berlin, Germany.
Nat Commun ; 12(1): 3818, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1279876
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Long Covid Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-24007-w

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Topics: Long Covid Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-24007-w