Institute of Virology, University of Leipzig, Leipzig, Germany.
Faculty of Life Sciences, University of Leipzig, Leipzig, Germany.
J Virol. 2018 Aug 16;92(17). doi: 10.1128/JVI.00934-18. Print 2018 Sep 1.
The flexible regulation of cellular metabolic pathways enables cellular adaptation to changes in energy demand under conditions of stress such as posed by a virus infection. To analyze such an impact on cellular metabolism, rubella virus (RV) was used in this study. RV replication under selected substrate supplementation with glucose, pyruvate, and glutamine as essential nutrients for mammalian cells revealed its requirement for glutamine. The assessment of the mitochondrial respiratory (based on the oxygen consumption rate) and glycolytic (based on the extracellular acidification rate) rate and capacity by respective stress tests through Seahorse technology enabled determination of the bioenergetic phenotype of RV-infected cells. Irrespective of the cellular metabolic background, RV infection induced a shift of the bioenergetic state of epithelial cells (Vero and A549) and human umbilical vein endothelial cells to a higher oxidative and glycolytic level. Interestingly there was a RV strain-specific, but genotype-independent demand for glutamine to induce a significant increase in metabolic activity. While glutaminolysis appeared to be rather negligible for RV replication, glutamine could serve as donor of its amide nitrogen in biosynthesis pathways for important metabolites. This study suggests that the capacity of RVs to induce metabolic alterations could evolve differently during natural infection. Thus, changes in cellular bioenergetics represent an important component of virus-host interactions and could complement our understanding of the viral preference for a distinct host cell population. RV pathologies, especially during embryonal development, could be connected with its impact on mitochondrial metabolism. With bioenergetic phenotyping we pursued a rather novel approach in virology. For the first time it was shown that a virus infection could shift the bioenergetics of its infected host cell to a higher energetic state. Notably, the capacity to induce such alterations varied among different RV isolates. Thus, our data add viral adaptation of cellular metabolic activity to its specific needs as a novel aspect to virus-host evolution. In addition, this study emphasizes the implementation of different viral strains in the study of virus-host interactions and the use of bioenergetic phenotyping of infected cells as a biomarker for virus-induced pathological alterations.
细胞代谢途径的灵活调节使细胞能够在应激条件下（如病毒感染）适应能量需求的变化。为了分析这种对细胞代谢的影响，本研究使用了风疹病毒（RV）。在选定的底物补充下，RV 在葡萄糖、丙酮酸和谷氨酰胺的存在下复制，这些是哺乳动物细胞的必需营养物质，这表明它对谷氨酰胺有需求。通过 Seahorse 技术进行的线粒体呼吸（基于耗氧率）和糖酵解（基于细胞外酸化率）的应激测试评估，使我们能够确定 RV 感染细胞的生物能量表型。无论细胞代谢背景如何，RV 感染都会导致上皮细胞（Vero 和 A549）和人脐静脉内皮细胞的生物能量状态向更高的氧化和糖酵解水平转变。有趣的是，RV 株具有特异性，而基因型则不依赖于谷氨酰胺，以诱导代谢活性的显著增加。虽然谷氨酰胺分解代谢似乎对 RV 复制的作用不大，但谷氨酰胺可以作为其生物合成途径中重要代谢物的酰胺氮供体。本研究表明，RV 在自然感染过程中诱导代谢改变的能力可能会有所不同。因此，细胞生物能量的变化是病毒-宿主相互作用的一个重要组成部分，并可以补充我们对病毒对特定宿主细胞群的偏好的理解。RV 病理学，特别是在胚胎发育期间，可能与其对线粒体代谢的影响有关。通过生物能量表型分析，我们在病毒学中采用了一种相当新颖的方法。这是首次表明病毒感染可以使受感染宿主细胞的生物能量向更高的能量状态转变。值得注意的是，不同 RV 分离株诱导这种改变的能力存在差异。因此，我们的数据增加了细胞代谢活性对病毒特定需求的适应性，作为病毒-宿主进化的一个新方面。此外，本研究强调了在研究病毒-宿主相互作用时使用不同的病毒株，并将感染细胞的生物能量表型作为病毒诱导的病理改变的生物标志物。
