Key Points ZIKV inhibits AMPK signaling and increases glycolysis to promote viral replication. AMPK potentiates antiviral immune response and inhibits ZIKV-induced glycolysis. AMPK ablation increases ZIKV replication and reduces innate antiviral responses. Visual Abstract Viruses are known to perturb host cellular metabolism to enable their replication and spread. However, little is known about the interactions between Zika virus (ZIKV) infection and host metabolism. Using primary human retinal vascular endothelial cells and an established human endothelial cell line, we investigated the role of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, in response to ZIKV challenge. ZIKV infection caused a time-dependent reduction in the active phosphorylated state of AMPK and of its downstream target acetyl-CoA carboxylase. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, and a specific AMPKα activator (GSK621) attenuated ZIKV replication. This activity was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK and the use of AMPKα−/− mouse embryonic fibroblasts provided further evidence that AMPK has an antiviral effect on ZIKV replication. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, OAS2, ISG15, and MX1) and inhibited inflammatory mediators (e.g., TNF-α and CCL5). Bioenergetic analysis showed that ZIKV infection evokes a glycolytic response, as evidenced by elevated extracellular acidification rate and increased expression of key glycolytic genes (GLUT1, HK2, TPI, and MCT4); activation of AMPK by AICAR treatment reduced this response. Consistent with this, 2-deoxyglucose, an inhibitor of glycolysis, augmented AMPK activity and attenuated ZIKV replication. Thus, our study demonstrates that the anti-ZIKV effect of AMPK signaling in endothelial cells is mediated by reduction of viral-induced glycolysis and enhanced innate antiviral responses.

中文翻译：

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AMP 激活的蛋白激酶通过增强先天抗病毒反应和抑制糖酵解来限制内皮细胞中寨卡病毒的复制

关键点 ZIKV 抑制 AMPK 信号并增加糖酵解以促进病毒复制。AMPK 增强抗病毒免疫反应并抑制 ZIKV 诱导的糖酵解。AMPK 消融增加 ZIKV 复制并减少先天抗病毒反应。众所周知，视觉抽象病毒会扰乱宿主细胞的新陈代谢，使其复制和传播。然而，对寨卡病毒 (ZIKV) 感染与宿主代谢之间的相互作用知之甚少。我们使用原代人视网膜血管内皮细胞和已建立的人内皮细胞系，研究了能量代谢的主要调节因子 AMP 活化蛋白激酶 (AMPK) 在应对 ZIKV 挑战时的​​作用。ZIKV 感染导致 AMPK 及其下游靶标乙酰辅酶 A 羧化酶的活性磷酸化状态随时间降低。使用 5-氨基咪唑-4-甲酰胺核糖核苷酸 (AICAR)、二甲双胍和特定的 AMPKα 激活剂 (GSK621) 对 AMPK 的药理学激活减弱了 ZIKV 复制。这种活性被 AMPK 抑制剂（化合物 C）逆转。慢病毒介导的 AMPK 敲低和使用 AMPKα-/- 小鼠胚胎成纤维细胞进一步证明 AMPK 对 ZIKV 复制具有抗病毒作用。与其抗病毒作用一致，AMPK 激活增强了具有抗病毒特性的基因（例如，IFN、OAS2、ISG15 和 MX1）的表达并抑制了炎症介质（例如，TNF-α 和 CCL5）。生物能学分析表明，ZIKV 感染会引起糖酵解反应，这可以通过细胞外酸化率升高和关键糖酵解基因（GLUT1、HK2、TPI 和 MCT4）的表达增加来证明；通过 AICAR 处理激活 AMPK 减少了这种反应。与此一致的是，糖酵解抑制剂 2-脱氧葡萄糖增强了 AMPK 活性并减弱了 ZIKV 复制。因此，我们的研究表明，内皮细胞中 AMPK 信号传导的抗 ZIKV 效应是通过减少病毒诱导的糖酵解和增强的先天抗病毒反应来介导的。