Uncovering and harnessing connected metabolic pathways essential to virus infection.

发现和利用病毒感染所必需的相关代谢途径。

• 批准号: 10475649
• 负责人: Bryan C Mounce
• 金额: $ 36.94万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475649
• 关键词: Affect; Anabolism; Biological Models; Bunyavirus Infections; Cell physiology; Cells; Cholesterol; Coxsackie Viruses; Dengue Virus; Detection; Distant; Enterovirus; Eukaryotic Cell; Family; Flavivirus; Genetic Transcription; Genome; Infection; La Crosse virus; Link; Lipids; Metabolic Pathway; Metabolism; Morbidity - disease rate; Pathway interactions; Polyamines; RNA Viruses; Rhinovirus; Rift Valley fever virus; Role; Structure; Therapeutic Intervention; Translations; Virion; Virus; Virus Diseases; Virus Replication; Work; Zika Virus; mortality; pathogen; small molecule

Project Summary / Abstract Polyamines are small molecules abundant in eukaryotic cells that function in transcription and translation. While these molecules are important for cellular function, emerging evidence suggests that polyamine metabolism is intricately linked to diverse metabolic pathways within the cell. The interconnectedness of metabolic pathways has significant consequences for cells, as well as pathogens. We previously demonstrated that polyamines support replication of diverse RNA viruses and that upon detection of infection, cells induce polyamine depletion. Polyamine depletion limits infection by bunyaviruses (Rift Valley fever virus [RVFV] and La Crosse virus [LACV]), flaviviruses (Zika virus [ZIKV] and dengue viruses), and enteroviruses (Coxsackievirus B3 [CVB3], rhinovirus), among several others. We hypothesize that these distinct virus families subvert cellular metabolism, specifically through polyamines, to support virus replication. Here, we will investigate (1) how viruses utilize polyamines at distinct stages of replication, (2) how viruses confront polyamine depletion, and (3) how polyamine biosynthesis connects to other metabolic pathways to support virus replication. We use the RVFV, ZIKV, and CVB3 model systems in our work because these viruses represent three evolutionarily distant viruses with different replicative and structural differences. While each of these viruses relies on polyamines for replication, we find that how they use polyamines is different. Now, we will expand on this work to understand the roles of distinct polyamines during virus infection, including roles in virion structure, cellular attachment, and genome replication. We will also use these model systems to understand how these viruses manipulate polyamine metabolism. Finally, we will investigate how the differences in polyamine utilization may reflect how polyamines affect other cellular metabolic pathways, including lipid and cholesterol synthesis. This work will illuminate the connectedness of polyamine biosynthesis to other metabolic pathways and how viruses rely on these interconnected pathways for successful replication. This work will highlight fundamental roles for polyamines in virus replication and in cellular metabolism.

项目摘要 /摘要 多胺是在转录和翻译中起作用的真核细胞中丰富的小分子。 尽管这些分子对于细胞功能很重要，但新兴的证据表明多胺 代谢与细胞内的不同代谢途径无关。相互联系 代谢途径对细胞以及病原体产生重大影响。我们以前证明了 多胺支持复制各种RNA病毒，并在检测到感染后诱导细胞 多胺消耗。多胺耗竭限制了邦雅病毒（Rift Valley Fever病毒[RVFV]和 La Crosse病毒[LACV]），黄病毒（Zika病毒[Zikv]和登革热病毒）和肠病毒 （Coxsackievivirus B3 [CVB3]，鼻病毒），等等。我们假设这些独特的病毒 家族颠覆了细胞代谢，特别是通过多胺，以支持病毒复制。 在这里，我们将研究（1）病毒在不同复制阶段如何利用多胺，（2）病毒如何 面对多胺消耗，（3）多胺生物合成如何连接到其他代谢途径 支持病毒复制。 我们在工作中使用RVFV，ZIKV和CVB3模型系统，因为这些病毒代表三个 具有不同复制和结构差异的进化较远的病毒。这些病毒中的每一个 依靠多胺进行复制，我们发现它们如何使用多胺是不同的。现在，我们将扩展 这项工作以了解不同多胺在病毒感染中的作用，包括病毒粒结构中的作用， 细胞附着和基因组复制。我们还将使用这些模型系统来了解这些 病毒操纵多胺代谢。最后，我们将研究多胺的差异 利用可能反映了多胺如何影响其他细胞代谢途径，包括脂质和胆固醇 合成。这项工作将阐明多胺生物合成与其他代谢途径的连接性 病毒如何依赖这些相互联系的途径成功复制。这项工作将突出显示 多胺在病毒复制和细胞代谢中的基本作用。