SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals.
SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals.
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DOI：
10.1038/s41467-021-24007-w
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发表时间：
2021-06-21
影响因子：
16.6
通讯作者：
Müller MA
中科院分区：
文献类型：
--
作者：
Gassen NC;Papies J;Bajaj T;Emanuel J;Dethloff F;Chua RL;Trimpert J;Heinemann N;Niemeyer C;Weege F;Hönzke K;Aschman T;Heinz DE;Weckmann K;Ebert T;Zellner A;Lennarz M;Wyler E;Schroeder S;Richter A;Niemeyer D;Hoffmann K;Meyer TF;Heppner FL;Corman VM;Landthaler M;Hocke AC;Morkel M;Osterrieder N;Conrad C;Eils R;Radbruch H;Giavalisco P;Drosten C;Müller MA
病毒操纵细胞代谢和大分子再循环过程，如自噬。代谢失调可能导致过度的炎症和自身免疫反应，如在严重和长期的COVID-19患者中观察到的那样。在这里，我们表明，SARS-CoV-2调节细胞代谢，减少自噬。因此，化合物驱动的自噬诱导限制了SARS-CoV-2的传播。详细地说，SARS-CoV-2感染的细胞显示出关键代谢物的积累，自噬抑制剂（AKT 1，SKP 2）的激活和负责自噬起始（AMPK，TSC 2，ULK 1），膜成核和吞噬细胞形成（BECN 1，VPS 34，ATG 14）的蛋白质的减少，以及自噬体-溶酶体融合（BECN 1，ATG 14寡聚体）。因此，吞噬细胞结合的自噬标记物LC 3B-II和P62积累，我们在仓鼠模型和COVID-19患者的肺样本中证实了这一点。患者来源的肺和粘膜样本的单核和单细胞测序显示，自噬和免疫基因的转录调控差异取决于细胞类型，疾病持续时间和SARS-CoV-2复制水平。通过外源性给予多胺亚精胺和精胺、选择性AKT 1抑制剂MK-2206和稳定BECN 1的驱虫药氯硝柳胺来靶向自噬途径，在体外抑制SARS-CoV-2的繁殖，IC 50值分别为136.7、7.67、0.11和0.13 μM。自噬诱导化合物减少了SARS-CoV-2在原代人肺细胞和肠类器官中的传播，强调了它们作为COVID-19治疗选择的潜力。病毒操纵宿主细胞途径以支持感染。在这里，作者表明SARS-CoV-2感染调节细胞代谢并限制自噬，并确定了病毒抑制的药物宿主途径。
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. 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.
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影响因子：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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