Uncovering and harnessing connected metabolic pathways essential to virus infection.

项目概要/摘要 多胺是真核细胞中丰富的小分子，在转录和翻译中起作用。 虽然这些分子对细胞功能很重要，但新出现的证据表明， 代谢与细胞内的多种代谢途径错综复杂地联系在一起。的相互关联性 代谢途径对细胞以及病原体具有重要的影响。我们先前表明 多胺支持多种RNA病毒的复制，并且在检测到感染时，细胞诱导 多胺耗竭多胺消耗限制了布尼亚病毒（裂谷热病毒[RVFV]和 拉克罗斯病毒[LACV]）、黄病毒（寨卡病毒[ZIKV]和登革热病毒）和肠道病毒 （柯萨奇病毒B3 [CVB 3]，鼻病毒），以及其他几种病毒。我们假设这些不同的病毒 家族破坏细胞代谢，特别是通过多胺，以支持病毒复制。 在这里，我们将研究（1）病毒如何利用多胺在不同阶段的复制，（2）病毒如何利用多胺在不同阶段的复制， 面对多胺耗竭，以及（3）多胺生物合成如何连接到其他代谢途径， 支持病毒复制。 我们在我们的工作中使用RVFV、ZIKV和CVB 3模型系统，因为这些病毒代表了三种 具有不同复制和结构差异的进化上遥远的病毒。虽然这些病毒中的每一种 依赖于多胺进行复制，我们发现它们如何使用多胺是不同的。现在，我们将扩展到 这项工作是为了了解不同的多胺在病毒感染过程中的作用，包括在病毒体结构中的作用， 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 利用率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的生物合成与其他代谢途径的联系 以及病毒如何依靠这些相互关联的途径成功复制。这项工作将突出 多胺在病毒复制和细胞代谢中的基本作用。

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.