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: 10450249
• 负责人: George A. Belov
• 金额: $ 37.93万
• 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/10450249
• 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 Infections; Environment; Epithelial; Eukaryota; FDA approved; Generations; Genes; Homeostasis; Human poliovirus; Hydrolysis; Infection; International; Knowledge; 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 感染特异性脂质代谢作为控制肠病毒感染的靶标 膜复制细胞器的发展是所有正链生命周期的关键步骤 真核生物的RNA病毒，包括肠病毒。复制的独特脂质和蛋白质组成 细胞器对于病毒酶复制机制的功能至关重要，并且可能 隐藏来自细胞抗病毒的传感器和效应器中包含dsRNA的复制复合物 回复。对于肠病毒，复制细胞器的结构和功能发展 需要对细胞脂质合成和膜代谢途径进行深刻的重新配置。最近 我们和其他人表明，多样的肠病毒普遍参与脂质液滴，动态细胞 调节脂质代谢的细胞器，以支持复制细胞器的发展。 新兴图片显示，肠病毒感染会导致：1）中性脂质的脂肪分解的激活 在脂质液滴中，释放游离的长链脂肪酸； 2）激活长链-Acyl-COA合成酶 必须将长链脂肪酸重新布置为代谢过程的活性，并以酰基-COAS的形式进行。 3）将新合成的酰基-COA重定向到结构磷脂的合成中，提供 膜扩展复制细胞器。我们假设自由长链脂肪的涌入 酸会触发感染细胞的脂质代谢的随后变化。我们的数据还表明 通过靶向脂质代谢的不同途径，可以使复制更加敏感 先天免疫机制，或专门消除受感染的细胞，提供有关该细胞的新观点 控制肠病毒感染。 在这里，我们组成了一个病毒学和脂质研究专家团队，用于使用生化，细胞生物学，创新性 显微镜和蛋白质组学方法研究了肠病毒感染细胞中脂质代谢的变化。 我们将重点介绍脂质液滴脂解和酰基-COA合成酶的参与度，因为它们 定义感染细胞中脂质代谢的景观。我们还将研究结构的作用 在保护复制络合物中扩展复制细胞器并探索 脂质合成途径的重新配置所赋予的感染细胞的漏洞。我们将使用 肠道和呼吸道上皮体外系统，用于研究重新布线脂质代谢在相关性中的作用 感染各种肠病毒的细胞。我们认为，这个项目将大大推动 感染细胞中脂质代谢的基本知识，与病毒学和细胞生物学广泛相关，以及 将开辟新的观点，以开发针对多种肠病毒有效的干预措施。