Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2022 Sep 12;13(1):5341. doi: 10.1038/s41467-022-33041-1.
The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified. The results show that ZIKV infection specifically increases the expression of genes enriched for lipid metabolism-related functions. ZIKV infection also increases the recruitment of sterol regulatory element-binding protein (SREBP) transcription factors to lipid gene promoters, while pharmacologic inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of DCs. Our data thus identify SREBP2-activated transcription as a mechanism for promoting ZIKV infection amenable to therapeutic targeting.
寨卡病毒（ZIKV）的出现对全球健康构成了威胁，突显了对寨卡病毒特异性疫苗和抗病毒治疗的需求尚未得到满足。寨卡病毒感染树突状细胞（DC），后者在激活先天和适应性抗病毒反应方面具有关键作用；然而，树突状细胞功能被颠覆以建立寨卡病毒感染的机制尚不清楚。在这里，我们开发了一种基因组学分析方法，可对感染寨卡病毒的与邻近未感染的原代人树突状细胞进行离散分析，从而提高识别寨卡病毒调节途径的灵敏度和特异性。结果表明，寨卡病毒感染特异性增加了富含脂质代谢相关功能的基因的表达。寨卡病毒感染还增加了固醇调节元件结合蛋白（SREBP）转录因子向脂质基因启动子募集的数量，而 SREBP2 的药理学抑制或基因沉默可抑制 DC 中的寨卡病毒感染。因此，我们的数据确定了 SREBP2 激活的转录作为促进寨卡病毒感染的机制，可通过治疗靶向进行干预。
