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: 10683729
• 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/10683729
• 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 多胺是真核细胞中丰富的小分子，具有转录和翻译功能。 虽然这些分子对细胞功能很重要，但越来越多的证据表明，多胺 新陈代谢与细胞内不同的代谢途径错综复杂地联系在一起。网络的互联性 代谢途径对细胞和病原体都有重大影响。我们之前演示过 多胺支持多种RNA病毒的复制，一旦检测到感染，细胞就会诱导 多胺耗尽。多胺耗竭限制了布尼亚病毒(裂谷热病毒[RVFV]和 La Crosse病毒[LACV])、黄病毒(寨卡病毒[ZIKV]和登革病毒)和肠道病毒 (柯萨奇病毒B3[柯萨奇病毒B3]，鼻病毒)，以及其他一些病毒。我们假设这些截然不同的病毒 家族颠覆细胞新陈代谢，特别是通过多胺，以支持病毒复制。 在这里，我们将研究(1)病毒如何在不同的复制阶段利用多胺，(2)病毒如何 面对多胺的消耗，以及(3)多胺的生物合成如何与其他代谢途径相联系，以 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种 进化上遥远的病毒，具有不同的复制和结构差异。虽然这些病毒中的每一个 依赖多胺进行复制，我们发现他们使用多胺的方式是不同的。现在，我们将扩展到 这项工作旨在了解不同的多胺在病毒感染过程中的作用，包括在病毒粒子结构中的作用， 细胞连接和基因组复制。我们还将使用这些模型系统来了解这些 病毒操控多胺代谢。最后，我们将调查多胺的差异是如何 利用多胺可能反映多胺如何影响其他细胞代谢途径，包括脂肪和胆固醇。 综合。这项工作将阐明多胺生物合成与其他代谢途径的联系。 以及病毒如何依赖这些相互连接的途径来成功复制。这项工作将突出 多胺在病毒复制和细胞代谢中的基础作用。

项目成果

Good cop, bad cop: Polyamines play both sides in host immunity and viral replication.

• DOI: 10.1016/j.semcdb.2022.12.004
• 发表时间: 2023-01
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Yazmin E Cruz-Pulido;Bryan C. Mounce

Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.

• DOI: 10.1021/acsinfecdis.2c00071
• 发表时间: 2022-08-12
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Mastrodomenico, Vincent;LoMascolo, Natalie J.;Cruz-Pulido, Yazmin E.;Cunha, Christina R.;Mounce, Bryan C.
• 通讯作者: Mounce, Bryan C.

Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro.

• DOI: 10.3390/v13020310
• 发表时间: 2021-02-16
• 期刊: Viruses
• 作者: Hulsebosch BM;Mounce BC
• 通讯作者: Mounce BC