Division of Pathway Medicine and Centre for Infectious Diseases, University of Edinburgh, Edinburgh, United Kingdom.
PLoS Biol. 2011 Mar;9(3):e1000598. doi: 10.1371/journal.pbio.1000598. Epub 2011 Mar 8.
Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNγ or β but not TNF, IL1β, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNβ treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNβ, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNβ treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy.
关于炎症过程在调节感染时的脂质代谢中的保护作用知之甚少。在这里，我们报告了固有免疫反应与固醇代谢网络调控之间的密切联系，其特征是通过干扰素调节环机制下调固醇生物合成。在对巨噬细胞全基因组脂质相关基因表达进行时间序列实验时，我们发现，在病毒感染或用 IFNγ或β而不是 TNF、IL1β 或 IL6 处理细胞后，完整的固醇途径会受到选择性和协调性的负调控。感染后对选定固醇代谢酶的蛋白质水平进行定量分析表明，抑制水平相似。使用基于脂质组学的测量方法对固醇代谢物水平进行实验测试表明，代谢产物减少。基于固醇途径的药理学和 RNAi 抑制实验，我们发现对病毒感染的保护作用增强，并且结合代谢物挽救实验，我们确定了固醇代谢网络的甲羟戊酸异戊二烯分支在他汀类药物或 IFNβ 治疗时的保护反应中的必要性。来自感染细胞的条件培养基实验支持分泌型 1 型干扰素（s）的参与足以在感染时减少固醇途径。此外，我们发现，感染含有主要 1 型干扰素 IFNβ 的基因敲除的原代巨噬细胞，只会导致固醇途径的部分抑制，而基因敲除所有 1 型干扰素家族成员的受体 ifnar1 或相关信号成分 tyk2，则会完全消除感染时固醇生物合成活性的降低。SREBP2 的蛋白水解裂解核形式（固醇生物合成的关键转录调节剂）的水平在感染和 IFNβ 处理时降低，无论是在蛋白质水平还是从头转录水平上都是如此。感染和 IFN 处理时 srebf2 基因转录的降低也被发现严格依赖于 ifnar1。总而言之，这些结果表明 1 型 IFN 信号对于感染时降低固醇代谢网络活性是必要且充分的，从而将固醇途径的调控与干扰素抗病毒防御反应联系起来。这些发现为固醇代谢与干扰素抗病毒反应之间建立了新的联系，并支持将先天免疫的宿主代谢调节剂作为一种潜在的抗病毒策略的想法。
