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| Item Type: | Article |
|---|---|
| Title: | SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals |
| Creators Name: | Gassen, N.C. and Papies, J. and Bajaj, T. and Emanuel, J. and Dethloff, F. and Chua, R.L. and Trimpert, J. and Heinemann, N. and Niemeyer, C. and Weege, F. and Hönzke, K. and Aschman, T. and Heinz, D.E. and Weckmann, K. and Ebert, T. and Zellner, A. and Lennarz, M. and Wyler, E. and Schroeder, S. and Richter, A. and Niemeyer, D. and Hoffmann, K. and Meyer, T.F. and Heppner, F.L. and Corman, V.M. and Landthaler, M. and Hocke, A.C. and Morkel, M. and Osterrieder, N. and Conrad, C. and Eils, R. and Radbruch, H. and Giavalisco, P. and Drosten, C. and Müller, M.A. |
| 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 IC(50) 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. |
| Keywords: | Animal Disease Models, Antinematodal Agents, Autophagosomes, Autophagy, Autophagy-Related Proteins, COVID-19, Cultured Cells, Lung, Metabolome, Niclosamide, Organoids, SARS-CoV-2, Spermidine, Spermine, Animals, Cricetinae, Chlorocebus aethiops |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| Page Range: | 3818 |
| Date: | 21 June 2021 |
| Official Publication: | https://doi.org/10.1038/s41467-021-24007-w |
| PubMed: | View item in PubMed |
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