Infection-specific lipid metabolism as a target to control enterovirus infections

感染特异性脂质代谢作为控制肠道病毒感染的目标

• 批准号: 10597236
• 负责人: George A. Belov
• 金额: $ 36.57万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597236
• 关键词: Acyl Coenzyme A; Antiviral Agents; Antiviral Response; Biochemical; Biological Assay; Biotinylation; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cells; Cellular biology; Cholesterol Esters; Coenzyme A; Coenzyme A Ligases; Complex; Data; Development; Diglycerides; Double-Stranded RNA; Drug Targeting; Enteral; Enterocytes; Enterovirus; Enterovirus 71; Enterovirus Infections; Environment; Epithelium; Esterification; Eukaryota; FDA approved; Generations; Genes; Homeostasis; Human poliovirus; Hydrolysis; Infection; International; Knowledge; Licensing; Life Cycle Stages; Ligase; Lipase; Lipid Mobilization; Lipid Peroxides; Lipid Synthesis Pathway; Lipids; Lipolysis; Measures; Membrane; Metabolic Pathway; Metabolism; Methods; Microscopy; Modeling; Monitor; Natural Immunity; Organelles; Pathway interactions; Peroxidases; Pharmaceutical Preparations; Phenotype; Phospholipids; Polyunsaturated Fatty Acids; Proteins; Proteome; Proteomics; Publishing; RNA Viruses; Reaction; Research; Resistance; Resistance development; Resources; Role; Route; Signal Pathway; Signal Transduction; Site; Speed; Structure; System; Triglycerides; Up-Regulation; Vaccines; Viral; Viral Physiology; Viral Proteins; Virus Replication; airway epithelium; cytokine; drug development; effective intervention; fatty acid metabolism; innovation; knockout gene; lipid metabolism; long chain fatty acid; membrane synthesis; mutant; protein protein interaction; recruit; respiratory; sensor; therapy development; transcriptome sequencing; virology

Project Summary Infection-specific lipid metabolism as a target to control enterovirus infections The development of the membranous replication organelles is a crucial step in the life cycle of all positive-strand RNA viruses of eukaryotes, including enteroviruses. The unique lipid and protein composition of the replication organelles is essential for the functioning of the viral enzymatic replication machinery, and the membranes likely hide the replication complexes containing dsRNA from the sensors and effectors of the cellular anti-viral response. In the case of enteroviruses, the structural and functional development of the replication organelles requires a profound reconfiguration of the cellular lipid synthesis and membrane metabolism pathways. Recently we and others demonstrated that diverse enteroviruses universally engage lipid droplets, dynamic cellular organelles that regulate the lipid metabolism, to support the development of the replication organelles. The emerging picture shows that enterovirus infection results in: 1) activation of lipolysis of neutral lipids stored in lipid droplets, liberating free long-chain fatty acids; 2) activation of long chain-acyl-CoA synthetases whose activity is necessary to re-route the long-chain fatty acids into metabolic processes in the form of acyl-CoAs, and 3) redirection of the newly-synthesized acyl-CoAs into the synthesis of structural phospholipids, providing membranes for the expansion of the replication organelles. We hypothesize that the influx of free long-chain fatty acids triggers the subsequent changes in the lipid metabolism of infected cells. Our data also demonstrate that by targeting different pathways of lipid metabolism it is possible to make the replication more sensitive to the innate immunity mechanisms, or to specifically eliminate the infected cells, providing a new perspective on the control of enterovirus infections. Here, we formed a team of experts in virology and lipid research to use biochemical, cell biology, innovative microscopy and proteomics methods to investigate the changes in lipid metabolism in enterovirus-infected cells. We will focus on the activation of lipid droplet lipolysis and engagement of acyl-CoA synthetases because they define the landscape of lipid metabolism in infected cells. We will also investigate the role of the structural expansion of the replication organelles in the protection of the replication complexes and explore the vulnerabilities of infected cells conferred by the reconfiguration of the lipid synthesis pathways. We will use enteric and respiratory airway epithelia ex-vivo systems to study the role of rewiring lipid metabolism in relevant cells upon infection of diverse enteroviruses. We believe that this project will significantly advance the fundamental knowledge of lipid metabolism in infected cells, broadly relevant for virology and cell biology, and will open new perspectives for the development of interventions effective against diverse enteroviruses.

项目摘要 肠道病毒特异性脂质代谢作为控制肠道病毒感染的靶点 膜复制细胞器的发育是所有正链复制细胞生命周期中的关键步骤， 真核生物的RNA病毒，包括肠道病毒。复制过程中独特的脂质和蛋白质组成 细胞器对于病毒酶复制机制的功能是必不可少的，并且细胞膜可能 隐藏含有dsRNA的复制复合物，使其不受细胞抗病毒药物的传感器和效应器的影响， 反应就肠道病毒而言，复制细胞器的结构和功能发展 需要细胞脂质合成和膜代谢途径的深刻重构。最近 我们和其他人证明，不同的肠道病毒普遍参与脂滴，动态细胞， 调节脂质代谢的细胞器，以支持复制细胞器的发育。 新出现的图片显示，肠道病毒感染导致：1）激活储存的中性脂质的脂解 在脂滴中，释放游离的长链脂肪酸; 2）激活长链酰基辅酶A合成酶， 活性对于将长链脂肪酸以酰基辅酶A的形式重新路由到代谢过程中是必要的，并且 3)将新合成的酰基-CoA重定向到结构磷脂的合成中， 用于复制细胞器扩张的膜。我们假设游离长链脂肪酸的流入 酸触发了受感染细胞脂质代谢的后续变化。我们的数据还表明， 通过靶向脂质代谢的不同途径，有可能使复制对脂质代谢更敏感。 先天免疫机制，或专门消除感染的细胞，提供了一个新的视角， 控制肠道病毒感染。 在这里，我们组建了一个病毒学和脂质研究专家团队，利用生物化学、细胞生物学、创新 显微镜和蛋白质组学方法来研究肠道病毒感染细胞中脂质代谢的变化。 我们将重点关注脂滴脂解的激活和酰基辅酶A合成酶的参与，因为它们 定义了受感染细胞中脂质代谢的景观。我们还将研究结构的作用， 在复制复合物的保护复制细胞器的扩张，并探讨 受感染细胞的脆弱性由脂质合成途径的重新配置所赋予。我们将使用 肠和呼吸道上皮细胞离体系统，以研究脂质代谢的重新布线在相关 细胞感染不同的肠道病毒。我们相信，该项目将大大推动 受感染细胞中脂质代谢的基础知识，与病毒学和细胞生物学广泛相关，以及 将为开发有效对抗多种肠道病毒的干预措施开辟新的前景。