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

Author

Listed:
  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • Anja Richter

    (Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    German Center for Infection Research (DZIF), partner site Charité)

  • Daniela Niemeyer

    (Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    German Center for Infection Research (DZIF), partner site Charité)

  • 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
    German Center for Neurodegenerative Diseases (DZNE) Berlin
    Cluster of Excellence, NeuroCure)

  • Victor M. Corman

    (Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    German Center for Infection Research (DZIF), partner site Charité)

  • Markus Landthaler

    (Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
    IRI Life Sciences, Institut für Biologie, Humboldt-Universität zu Berlin)

  • 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
    German Cancer Consortium (DKTK) Partner Site Berlin, German Cancer Research Center (DKFZ))

  • Nikolaus Osterrieder

    (Institute of Virology, Freie Universität Berlin
    Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong)

  • 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
    German Center for Lung Research (DZL)
    Heidelberg University Hospital and BioQuant)

  • 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
    German Center for Infection Research (DZIF), partner site Charité)

  • Marcel A. Müller

    (Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
    German Center for Infection Research (DZIF), partner site Charité
    Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University)

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.

Suggested Citation

  • 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 A, 2021. "SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24007-w
    DOI: 10.1038/s41467-021-24007-w
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    Cited by:

    1. Shouheng Jin & Xing He & Ling Ma & Zhen Zhuang & Yiliang Wang & Meng Lin & Sihui Cai & Lu Wei & Zheyu Wang & Zhiyao Zhao & Yaoxing Wu & Lin Sun & Chunwei Li & Weihong Xie & Yong Zhao & Zhou Songyang &, 2022. "Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Maik Pietzner & Robert Lorenz Chua & Eleanor Wheeler & Katharina Jechow & Julian D. S. Willett & Helena Radbruch & Saskia Trump & Bettina Heidecker & Hugo Zeberg & Frank L. Heppner & Roland Eils & Mar, 2022. "ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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