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SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals
- Source :
- Nat Commun, Nature Communications 12(1), 3818 (2021). doi:10.1038/s41467-021-24007-w, Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021), Nature Communications
- Publication Year :
- 2021
-
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.<br />Viruses manipulate host cell pathways to support infection. Here the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition.
- Subjects :
- Cancer Research
Spermidine
viruses
Science
virology [COVID-19]
Autophagy-Related Proteins
drug therapy [COVID-19]
pharmacology [Spermidine]
metabolism [Lung]
pharmacology [Spermine]
Article
pathology [COVID-19]
metabolism [Autophagy-Related Proteins]
metabolism [SARS-CoV-2]
Cricetinae
Macroautophagy
Chlorocebus aethiops
Autophagy
Animals
Humans
virology [Lung]
Lung
metabolism [COVID-19]
Cells, Cultured
pathology [Lung]
SARS-CoV-2
Antinematodal Agents
Autophagosomes
COVID-19
Cellular metabolism
metabolism [Autophagosomes]
COVID-19 Drug Treatment
isolation & purification [SARS-CoV-2]
Organoids
Disease Models, Animal
Metabolome
pharmacology [Niclosamide]
Niclosamide
Spermine
Macromolecule recycling processes
ddc:500
pharmacology [Antinematodal Agents]
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nat Commun, Nature Communications 12(1), 3818 (2021). doi:10.1038/s41467-021-24007-w, Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021), Nature Communications
- Accession number :
- edsair.doi.dedup.....1dbe213434fcb363641a7a2287aa8abb