Publikationsdatenbank

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals (2021)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Gassen, Nils C.

Papies, Jan

Bajaj, Thomas

Emanuel, Jackson

Dethloff, Frederik

Chua, Robert Lorenz

Trimpert, Jakob (WE 5)

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 (WE 5)

Conrad, Christian

Eils, Roland

Radbruch, Helena

Giavalisco, Patrick

Drosten, Christian

Müller, Marcel A.

Quelle

Nature Communications

Bandzählung: 12

Heftzählung: 1

Seiten: Article number: 3818

ISSN: 2041-1723

Sprache

Englisch

Verweise

URL (Volltext): https://www.nature.com/articles/s41467-021-24007-w

DOI: 10.1038/s41467-021-24007-w

Pubmed: 34155207

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.