Mechanisms and consequences of metabolic manipulation by human cytomegalovirus

描述（由申请人提供）：人类巨细胞病毒（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。它是出生缺陷的主要原因，对免疫抑制的人来说是一种危及生命的机会性因素，也是某些癌症的可能辅助因素。利用基于液相色谱-质谱的代谢组学和同位素示踪剂，我们发现HCMV深刻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。这些代谢变化让人想起癌症中发生的变化。我们比较了HCMV和单纯疱疹病毒-1，发现后者的代谢作用虽然也很强，但与HCMV有很大的不同。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的成功复制依赖于多种代谢酶。乙酰辅酶a羧化酶、延长酶（ELOVLs）和酰基辅酶a合成酶抑制剂可阻断HCMV子代的产生。这些酶是产生长链脂肪酸所必需的，我们最近发现HCMV病毒粒子的包膜在这种脂肪酸尾部富集了大约10倍。因此，HCMV的生命周期需要合成特定的脂类。由于脂质生物合成酶抑制剂安全且耐受性良好，

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.