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. 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.
【저자키워드】 SARS-CoV-2, Macroautophagy, 【초록키워드】 COVID-19, Treatment, SARS-COV-2 infection, Sequencing, Infection, AKT1, lung, in vitro, autophagy, metabolism, Protein, polyamines, AMPK, virus inhibition, pathway, membrane, cellular metabolism, metabolites, inhibitor, disease, SARS-CoV-2 replication, single-cell, COVID-19 patients, niclosamide, mucosal, administration, Inflammatory, Autoimmune response, Skp2, Intestinal Organoids, cell type, host cell, spermidine, spermine, Support, reduction, Activation, infected cells, accumulation, Compound, transcriptional regulation, SARS-CoV-2 propagation, SARS-CoV-2-infected cells, selective, targeting, immune genes, Ulk1, autophagy markers, oligomers, Host, BECN1, limit, Cell, MK-2206, immune gene, ATG14, autophagic pathways, TSC2, responsible, identify, modulate, reduce, accumulate, autophagic pathway, autophagy marker, human lung cell, inhibit SARS-CoV-2, intestinal organoid, SARS-CoV-2-infected cell, 【제목키워드】 Antiviral, dysregulation,