Department of Microbiology, University of Washington, Seattle, Washington, USA.
J Virol. 2014 Apr;88(8):4366-74. doi: 10.1128/JVI.03134-13. Epub 2014 Feb 5.
Viruses require host cell metabolism to provide the necessary energy and biosynthetic precursors for successful viral replication. Vaccinia virus (VACV) is a member of the Poxviridae family, and its use as a vaccine enabled the eradication of variola virus, the etiologic agent of smallpox. A global metabolic screen of VACV-infected primary human foreskin fibroblasts suggested that glutamine metabolism is altered during infection. Glutamine and glucose represent the two main carbon sources for mammalian cells. Depriving VACV-infected cells of exogenous glutamine led to a substantial decrease in infectious virus production, whereas starving infected cells of exogenous glucose had no significant impact on replication. Viral yield in glutamine-deprived cells or in cells treated with an inhibitor of glutaminolysis, the pathway of glutamine catabolism, could be rescued by the addition of multiple tricarboxylic acid (TCA) cycle intermediates. Thus, VACV infection induces a metabolic alteration to fully rely on glutamine to anaplerotically maintain the TCA cycle. VACV protein synthesis, but not viral transcription, was decreased in glutamine-deprived cells, which corresponded with a dramatic reduction in all VACV morphogenetic intermediates. This study reveals the unique carbon utilization program implemented during poxvirus infection and provides a potential metabolic pathway to target viral replication.
Viruses are dependent on the metabolic machinery of the host cell to supply the energy and molecular building blocks needed for critical processes including genome replication, viral protein synthesis, and membrane production. This study investigates how vaccinia virus (VACV) infection alters global cellular metabolism, providing the first metabolomic analysis for a member of the poxvirus family. Unlike most viruses examined to date, VACV does not activate glycolysis, and exogenous glucose is not required for maximal virus production. Instead, VACV requires exogenous glutamine for efficient replication, and inhibition of glutamine metabolism effectively blocks VACV protein synthesis. This study defines a major metabolic perturbation essential for the replication of a poxvirus and may lead to the discovery of novel antiviral therapies based on metabolic inhibitors.
病毒需要宿主细胞代谢来提供成功复制所需的必要能量和生物合成前体。牛痘病毒（VACV）是痘病毒科的成员，其作为疫苗的使用使天花病毒（导致天花的病原体）得以根除。对感染原代人包皮成纤维细胞的 VACV 的全基因组代谢筛选表明，感染过程中谷氨酸代谢发生改变。谷氨酸和葡萄糖是哺乳动物细胞的两种主要碳源。剥夺感染 VACV 的细胞外源性谷氨酸会导致传染性病毒产量大幅下降，而耗尽感染细胞外源性葡萄糖对复制没有显著影响。在缺乏谷氨酰胺的细胞或用谷氨酰胺分解代谢途径的抑制剂处理的细胞中，病毒产量可以通过添加多种三羧酸（TCA）循环中间产物来挽救。因此，VACV 感染诱导代谢改变，完全依赖谷氨酰胺来维持 TCA 循环的碳同化。在缺乏谷氨酰胺的细胞中，VACV 蛋白合成而非病毒转录减少，这与所有 VACV 形态发生中间产物的急剧减少相对应。这项研究揭示了痘病毒感染过程中独特的碳利用方案，并为靶向病毒复制提供了一种潜在的代谢途径。
病毒依赖宿主细胞的代谢机制来提供包括基因组复制、病毒蛋白合成和膜产生在内的关键过程所需的能量和分子构建块。本研究调查了牛痘病毒（VACV）感染如何改变细胞的整体代谢，为痘病毒家族的一个成员提供了第一个代谢组学分析。与迄今为止研究的大多数病毒不同，VACV 不会激活糖酵解，外源性葡萄糖不是产生最大病毒产量所必需的。相反，VACV 复制需要外源性谷氨酰胺，而抑制谷氨酰胺代谢可有效阻断 VACV 蛋白合成。这项研究定义了一个对痘病毒复制至关重要的主要代谢扰动，并可能导致基于代谢抑制剂的新型抗病毒疗法的发现。
