Mechanisms and consequences of metabolic manipulation by human cytomegalovirus

人类巨细胞病毒代谢操纵的机制和后果

• 批准号: 8343995
• 负责人: JOSHUA D RABINOWITZ
• 金额: $ 55.43万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8343995
• 关键词: Acetyl-CoA Carboxylase; Address; Adult; Antiviral Agents; Area; Binding; Biochemical; Biochemical Pathway; Biochemistry; Biological Assay; Biology; Carbon; Cells; Cellular Stress Response; Citric Acid Cycle; Coenzyme A Ligases; Computer Simulation; Congenital Abnormality; Cytomegalovirus; Cytomegalovirus Infections; DNA Viruses; Data; Dependence; Disease; Environment; Enzymes; Event; Family; Fatty Acids; Fatty-acid synthase; Foundations; Generations; Glycolysis; Herpesviridae; Herpesvirus 1; Human; Immunocompromised Host; Infection; Infection Control; Isotopes; Lecithin; Life; Life Cycle Stages; Lipids; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Modification; Monitor; Pathway interactions; Pharmaceutical Preparations; Phosphatidylethanolamine; Phospholipids; Physiological; Population; Production; Proteins; Proteomics; Regulation; Role; Stress; Structure; Systems Biology; Tail; Testing; Time; Tracer; Triglycerides; Very Long Chain Fatty Acid; Viral; Virion; Virus; adenylate kinase; base; cofactor; inhibitor/antagonist; insight; lipid biosynthesis; lipid metabolism; liquid chromatography mass spectrometry; macromolecule; metabolomics; multidisciplinary; neonate; novel; pathogen; phosphatidylethanolamine; programs; virology

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV), a herpes virus, is a ubiquitous human pathogen that infects over 60% of the adult population. It is a major cause of birth defects, a life-threatening opportunistic agent in immuno-suppressed people, and a possible cofactor in certain cancers. Using liquid chromatography-mass spectrometry-based metabolomics together with isotope tracers, we have discovered that HCMV profoundly up-regulates many host cell metabolic pathways, including glycolysis, the TCA cycle, and lipid biosynthesis. These metabolic changes are evocative of those occurring in cancer. We have compared HCMV and herpes simplex virus-1, and found that the metabolic effects of the latter virus, while also strong, are quite different from those of HCMV. This indicates that different related viruses encode distinct programs for host cell metabolic hijacking. Importantly, we have used siRNAs and drugs to show that successful HCMV replication depends on multiple metabolic enzymes. Inhibitors of acetyl-CoA carboxylase, elongases (ELOVLs) and acyl-CoA synthetases block the production of HCMV progeny. These enzymes are needed to produce very long chain fatty acids, and we have recently discovered that the envelope of HCMV virions is enriched about 10-fold in such fatty acid tails. Thus, HCMV's life cycle requires synthesis of specific lipid species. As inhibitors of lipid biosynthetic enzymes can be safe and well tolerated, the sensitivity of HCMV to host cell lipid production may reflect a therapeutically important metabolic vulnerability. The major metabolic effects of HCMV raise critical fundamental questions: How does HCMV alter host cell metabolism? Which specific lipids does HCMV require? How do these contribute to viral replication? We propose to address these questions using a multidisciplinary combination of virology, biochemistry and systems biology. Specifically, we will: (i) assess the program of lipid metabolic changes induced by HCMV and determine how drugs that block specific metabolic enzymes needed by the virus alter this program; (ii) investigate the mechanism by which HCMV alters metabolism; and (iii) determine how the metabolic changes support HCMV replication. These studies address an important and understudied area of HCMV biology, they will advance fundamental understanding of metabolic regulation, and they will lay the foundation for the discovery of novel anti-virals. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus (HCMV) is a major cause of birth defects, a life-threatening opportunistic agent in immuno suppressed people, and a possible cofactor in certain cancers. The host metabolic environment is dramatically altered during infection with HCMV. The virus induces many metabolic pathways, with several lipid biosynthetic pathways essential for the production of virus progeny. We will explore the means by which the virus turns on these pathways, and the ways in which they contribute to viral replication. Our results will provide new insights into mechanisms underlying HCMV infection, information essential to our ultimate ability to develop new therapies and control infections.

描述（由申请人提供）：疱疹病毒人类巨细胞病毒（HCMV）是一种无处不在的人类病原体，可感染超过60％的成人人群的病原体。这是造成先天缺陷的主要原因，被免疫抑制人的威胁生命的机会主义者，以及某些癌症中可能的辅助因子。使用基于液相色谱 - 质谱法的代谢组学以及同位素示踪剂，我们发现HCMV深刻地上调了许多宿主细胞代谢途径，包括糖酵解，TCA循环和脂质生物合成。这些代谢变化是癌症中发生的变化。我们已经比较了HCMV和单纯疱疹病毒-1，发现后一种病毒的代谢作用虽然也很强，但与HCMV的代谢作用完全不同。这表明不同的相关病毒编码不同的程序，以用于宿主细胞代谢劫持。重要的是，我们使用siRNA和药物来表明成功的HCMV复制取决于多种代谢酶。乙酰辅酶A羧化酶，延伸酶（Elovls）和酰基-COA合成酶的抑制剂阻止了HCMV后代的产生。需要这些酶来产生非常长的链脂肪酸，并且我们最近发现，在这种脂肪酸尾巴中，HCMV病毒体的包膜富集了约10倍。因此，HCMV的生命周期需要合成特定的脂质物种。由于脂质生物合成酶的抑制剂可以安全且耐受性良好，因此 HCMV对宿主细胞脂质产生的敏感性可能反映出具有治疗意义的代谢脆弱性。 HCMV的主要代谢作用提出了关键的基本问题：HCMV如何改变宿主细胞代谢？ HCMV需要哪些特定的脂质？这些如何导致病毒复制？我们建议使用病毒学，生物化学和系统生物学的多学科组合来解决这些问题。具体而言，我们将：（i）评估HCMV诱导的脂质代谢变化的程序，并确定如何阻止病毒所需的特定代谢酶的药物改变该程序； （ii）研究HCMV改变新陈代谢的机制； （iii）确定代谢变化如何支持HCMV复制。这些研究涉及HCMV生物学的一个重要且研究的领域，它们将提高对代谢调节的基本理解，并将为发现新型抗病毒的基础奠定基础。 公共卫生相关性：人类巨细胞病毒（HCMV）是造成先天缺陷的主要原因，抑制免疫人员的生命的机会主义者，以及某些癌症中可能的辅助因子。 HCMV感染期间，宿主代谢环境发生了巨大改变。该病毒诱导许多代谢途径，几种脂质生物合成途径对于生产病毒后代必不可少。我们将探讨病毒在这些途径上开启的手段以及它们对病毒复制的贡献的方式。我们的结果将为您开发新疗法和控制感染的最终能力至关重要的信息提供有关HCMV感染基础机制的新见解。