Mechanisms and consequences of metabolic manipulation by human cytomegalovirus

描述（由申请方提供）：人巨细胞病毒（HCMV）是一种疱疹病毒，是一种普遍存在的人类病原体，感染超过60%的成年人群。它是出生缺陷的主要原因，是免疫抑制人群中威胁生命的机会性因子，也是某些癌症的可能辅助因子。使用液相色谱-质谱法为基础的代谢组学与同位素示踪剂一起，我们已经发现，HCMV深刻上调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。这些代谢变化与癌症中发生的代谢变化相似。我们比较了HCMV和单纯疱疹病毒-1，发现后者病毒的代谢效应虽然也很强，但与HCMV的代谢效应完全不同。这表明不同的相关病毒编码不同的宿主细胞代谢劫持程序。重要的是，我们已经使用siRNA和药物来证明HCMV的成功复制取决于多种代谢酶。乙酰辅酶A羧化酶、延长酶（acetyl-CoA carboxylase，elongases，ECOVL）和酰基辅酶A合成酶的抑制剂可阻断HCMV子代的产生。这些酶是产生非常长链的脂肪酸所必需的，我们最近发现HCMV病毒体的包膜富含约10倍的这种脂肪酸尾。因此，HCMV的生命周期需要特定脂质种类的合成。由于脂质生物合成酶的抑制剂可以是安全和良好耐受的， HCMV对宿主细胞脂质产生的敏感性可能反映了治疗上重要的代谢脆弱性。HCMV的主要代谢效应提出了关键的基本问题：HCMV如何改变宿主细胞的代谢？HCMV需要哪些特定的脂质？这些是如何促进病毒复制的？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程序，并确定阻断病毒所需的特定代谢酶的药物如何改变该程序;（ii）研究HCMV改变代谢的机制;（iii）确定代谢变化如何支持HCMV复制。这些研究解决了HCMV生物学的一个重要和未充分研究的领域，它们将推进对代谢调节的基本理解，并为发现新的抗病毒药物奠定基础。

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.