Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism

病毒与代谢：病毒感染和“病毒胰岛素”对宿主代谢的影响

作者：Khyati Girdhar,* Amaya Powis,* Amol Raisingani,* Martina Chrudinová, Ruixu Huang, Tu Tran, Kaan Sevgi, Yusuf Dogus Dogru, and Emrah Altindis

摘要：Over the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.

在过去的几十年里，人们一直在努力了解病毒与宿主代谢之间的相互影响。一些研究阐明了病毒感染操纵代谢途径的机制，包括葡萄糖、脂肪酸、蛋白质和核苷酸代谢。生命树中的这些代谢途径在进化上是保守的，对宿主的营养利用和能量生产非常重要。在这篇综述中，作者聚焦于宿主葡萄糖、谷氨酰胺和脂肪酸代谢，并重点介绍不同病毒调控宿主代谢途径以利于其复制。作者还探讨了一种新的病毒激素系统，即病毒模拟宿主激素来操纵宿主内分泌系统。作者讨论了病毒胰岛素/IGF-1样多肽（viral insulin/IGF-like peptides (VILPs)）及其对宿主代谢的潜在影响。总之，这些以细胞信号通路为靶点的发病机制建立了宿主与病毒蛋白之间的多维互作网络。定义并更好地理解这些机制将有助于我们开发新的治疗工具来防治病毒感染。

关键词：viruses, viral insulins, metabolism, glycolysis, lipid metabolism, glutaminolysis

病毒是世界上最丰富和分布最广的生物，具有多样的遗传物质和感染不同物种的能力。由于共同进化，病毒已经发展出各种机制来促进其自身复制。其中一种重要机制是通过破坏关键代谢途径和靶向代谢主调节蛋白来操纵/劫持宿主代谢。代谢通路参与协调细胞信号转导的主要决策过程；基因转录以及这些途径的精确调控对生物体至关重要。因此，病毒已经进化出靶向这些途径的手段并改变宿主的代谢。在过去的三十年里，一些研究团队还探索并确定了病毒增加细胞中的大分子合成，包括升高葡萄糖和脂肪酸水平，从而进行自我复制的机制。在这篇综述中，作者探讨了人类或其他动物病毒对宿主代谢途径的操纵/调控。该综述涵盖了已经确定病毒操控代谢信号确切机制的研究；成功表征这些病毒调控的信号通路有可能成为治疗病毒感染性疾病的关键。

Glucose metabolism and related signaling pathways are altered by viruses. Upon infection, there is an increase in the rate of glycolysis that is mainly accomplished by an increase in GLUT activity, rate-limiting glycolytic enzyme activity, and several signaling proteins and transcription factors.

Glutaminolysis signaling and related pathways are altered by viruses. Viruses increase glutaminolysis by targeting the glutamine transporter (SLC1A5/SLC7A5) and the activity and expression of the main enzymes GLS, GDH1, and ASAT to establish infection. Red type indicates main glutamine metabolism. 

Lipid metabolism and related pathways are altered by viruses. Upon infection, there is an increase in lipid synthesis, which is mediated by increasing the activity of main fatty acid synthesis enzymes such as ACC and FASN and transcription factors such as SREBP. Moreover, this figure also represents virus modulation of beta-oxidation and lipid droplet formation. 

Potential effects of VILPs on the host cell metabolism. We hypothesize that upon infection, VILPs will be translated and secreted by the host cells and act on a target cell in an autocrine (a), paracrine (b), or endocrine (c) manner. In the target cells, VILP may activate several aspects of insulin/IGF signaling and alter several pathways regulating carbohydrate metabolism, cell growth, proliferation, and apoptosis.

总结与展望：

    病毒对宿主代谢的调节是病毒复制和存活的重要组成部分。由于该领域已完成的研究数量非常有限，因此无法确定某些特定类别的病毒是否针对特定的宿主途径。例如，多种病毒都以P13K/AMPK/mTOR等信号通路为靶点操控宿主葡萄糖代谢。病毒还激活转录因子，如Myc、SREBP和HIF-1α，以促进其在宿主细胞中的复制和存活。抑制这些信号通路和几种代谢酶可以减少病毒在体内外的复制。此外，VILP的发现和表征为宿主-病原之间的相互作用开辟了一条新路径；在这种相互作用中，病毒能够模拟直接调节宿主新陈代谢的激素。更好地了解针对宿主新陈代谢的病毒机制将有助于我们更好地了解病毒的发病机制，并有可能为设计新型抗病毒疗法开辟新的途径。我们对病毒改变的这些信号通路及其对宿主的影响的了解仍然非常有限，需要进一步探索。

原文链接：https://www.annualreviews.org/doi/10.1146/annurev-virology-091919-102416

           https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175272/ 

Viral hijacking of cellular metabolism

病毒劫持细胞代谢

作者：Thaker SK, Ch'ng J, Christofk HR.

摘要： This review discusses the current state of the viral metabolism field and gaps in knowledge that will be important for future studies to investigate. We discuss metabolic rewiring caused by viruses, the influence of oncogenic viruses on host cell metabolism, and the use of viruses as guides to identify critical metabolic nodes for cancer anabolism. We also discuss the need for more mechanistic studies identifying viral proteins responsible for metabolic hijacking and for in vivo studies of viral-induced metabolic rewiring. Improved technologies for detailed metabolic measurements and genetic manipulation will lead to important discoveries over the next decade.

展望：While many studies have demonstrated that viruses reprogram cell metabolism and rely on metabolic changes for optimal virus replication in vitro, significant work remains to determine mechanistically what viral proteins interact with host cell machinery to induce such alterations and characterize whether the same metabolic perturbations occur during infection in vivo. Additionally, it will be interesting for future studies to determine whether there is different viral affinity for and replication across tissue types depending on the metabolic environment; whether differential metabolic reprogramming by a virus across multiple species impacts how specific species cope with viral replication; and whether or not viral-induced metabolic reprogramming contributes to oncogenesis. The future is certainly ripe for discovery in the viral metabolism field.

原文：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637495/

 参考文献：

1. Girdhar, K., Powis, A., Raisingani, A., Chrudinová, M., Huang, R., Tran, T., Sevgi, K., Dogus Dogru, Y., & Altindis, E. (2021). Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism. Annual review of virology, 8(1), 373–391. https://doi.org/10.1146/annurev-virology-091919-102416   

2. Thaker SK, Ch'ng J, Christofk HR. Viral hijacking of cellular metabolism. BMC Biol. 2019 Jul 18;17(1):59. https://doi.org/10.1186/s12915-019-0678-9