Institute of Virology, Philipps-University Marburg, Marburg, Germany.
Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany.
Commun Biol. 2024 Sep 5;7(1):1089. doi: 10.1038/s42003-024-06776-4.
Viruses depend on host metabolic pathways and flaviviruses are specifically linked to lipid metabolism. During dengue virus infection lipid droplets are degraded to fuel replication and Zika virus (ZIKV) infection depends on triglyceride biosynthesis. Here, we systematically investigated the neutral lipid-synthesizing enzymes diacylglycerol O-acyltransferases (DGAT) and the sterol O-acyltransferase (SOAT) 1 in orthoflavivirus infection. Downregulation of DGAT1 and SOAT1 compromises ZIKV infection in hepatoma cells but only SOAT1 and not DGAT inhibitor treatment reduces ZIKV infection. DGAT1 interacts with the ZIKV capsid protein, indicating that protein interaction might be required for ZIKV replication. Importantly, inhibition of SOAT1 severely impairs ZIKV infection in neural cell culture models and cerebral organoids. SOAT1 inhibitor treatment decreases extracellular viral RNA and E protein level and lowers the specific infectivity of virions, indicating that ZIKV morphogenesis is compromised, likely due to accumulation of free cholesterol. Our findings provide insights into the importance of cholesterol and cholesterol ester balance for efficient ZIKV replication and implicate SOAT1 as an antiviral target.
病毒依赖于宿主的代谢途径，黄病毒与脂质代谢特别相关。在登革热病毒感染期间，脂滴被降解以支持复制，而寨卡病毒（ZIKV）感染依赖于甘油三酯的生物合成。在这里，我们系统地研究了正黄病毒感染中的中性脂质合成酶二酰基甘油 O-酰基转移酶（DGAT）和固醇 O-酰基转移酶（SOAT）1。下调 DGAT1 和 SOAT1 会损害肝细胞中的 ZIKV 感染，但只有 SOAT1 而不是 DGAT 抑制剂处理会降低 ZIKV 感染。DGAT1 与 ZIKV 衣壳蛋白相互作用，表明蛋白相互作用可能是 ZIKV 复制所必需的。重要的是，SOAT1 抑制剂严重损害了神经细胞培养模型和脑类器官中的 ZIKV 感染。SOAT1 抑制剂处理降低了细胞外病毒 RNA 和 E 蛋白水平，并降低了病毒粒子的特异性感染力，表明 ZIKV 形态发生受损，可能是由于游离胆固醇的积累。我们的研究结果提供了有关胆固醇和胆固醇酯平衡对有效 ZIKV 复制的重要性的见解，并暗示 SOAT1 是一种抗病毒靶标。
