Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism

项目总结 人巨细胞病毒(HCMV)是一种引起人类疾病和死亡的疱疹病毒。 免疫功能受损，是导致先天性残疾的主要原因。人巨细胞病毒复制需要脂质。 由于巨细胞病毒不编码代谢网络，病毒的复制依赖于宿主的脂类代谢。 然而，关于HCMV如何重新编程宿主代谢以确保病毒所需的脂类，人们知之甚少。 进行复制。我们的总体目标是了解调节脂质合成的病毒与宿主的相互作用 对于复制巨细胞病毒来说是必不可少的。最近，我们发现hcmv感染会导致血脂升高。 脂肪合成和脂肪丰度的增加。在这里，我们证明了巨细胞病毒感染诱导合成 至少20种以前未被描述的脂类，是感染细胞所特有的。这些独特的脂类大多是磷脂 具有超长链脂肪酸尾巴(PL-VLCFA)。本申请中讨论的PL-VLCFA包括 在我们的工作之外，对巨细胞病毒生物学的研究普遍不足和未被研究。而较短的足总尾巴 经过充分研究，我们对VLCFAs尾巴和我们在HCMV中观察到的一样长的脂类知之甚少 感染，包括它们在生物膜中的行为。这背后的分子机制 HCMV诱导的宿主脂质体的扩张和新生成的脂类的功能作用 很大程度上是未知的。 我们发现，HCMV pUL37x1和pUL38蛋白促进PL-VLCFA合成，为 为了解巨细胞病毒重新编程脂质合成的机制奠定了基础。PUL37x1和 PUL38分别诱导钙和mTOR信号传导。我们有初步数据表明，压力 与这些信号通路相关的反应参与了HCMV的脂质重塑。我们假设 PUL37x1和pUL38利用Ca~(2+)和mTOR信号促进PC-VLCFAs的合成 人巨细胞病毒复制。我们将通过确定pUL37x1和pUL38 促进PL-VLCFA的合成(目标1)并确定HCMV所需的PL-VLCFA合成酶 复制和PL-VLCFAs在感染中的作用(目标2)。这些研究将通过以下方式确定机制 哪种HCMV与宿主相互作用，创造了独特的脂质环境，促进了我们对HCMV的了解 新陈代谢的重新编程。此外，这些研究将确定PC-VLCFA的生物学功能 进一步了解了HCMV感染所需的脂类。确定 人巨细胞病毒诱导脂代谢重编程的机制及PC-VLCFAs的功能 人类巨细胞病毒生物学方面的先进知识需要确定治疗感染的新靶点。

PROJECT SUMMARY Human cytomegalovirus (HCMV) is a herpesvirus that causes disease and death in the immunocompromised and is a leading cause of congenital disabilities. HCMV replication requires lipids. Since HCMV does not encode a metabolic network, virus replication depends on host lipid metabolism. However, little is known about how HCMV reprograms host metabolism to ensure lipids required for virus replication are made. Our overall goal is to understand the virus-host interactions that regulate lipid synthesis essential for HCMV replication. Recently, we showed that HCMV infection results in an increase in lipid synthesis and a rise in lipid abundances. Here we demonstrate that HCMV infection induces the synthesis of at least 20 previously undescribed lipids unique to infected cells. Most of these unique lipids are phospholipids with very long-chain fatty acid tails (PL-VLCFAs). The PL-VLCFAs discussed in this application are understudied in general and unstudied in HCMV biology beyond our work. While shorter FA tails have been well-studied, we know little about lipids with VLCFAs tails that are as long as those we observe in HCMV infection, including how they will behave in a biological membrane. The molecular mechanisms underlying this HCMV-induced expansion in the host lipidome and the functional roles of the newly generated lipids are largely unknown. We discovered that HCMV pUL37x1 and pUL38 proteins promote PL-VLCFA synthesis, laying the foundation for understanding the mechanisms by which HCMV reprograms lipid synthesis. pUL37x1 and pUL38 induce Ca2+ and mTOR signaling, respectively. We have preliminary data suggesting that stress responses related to these signaling pathways contribute to HCMV remodeling of lipids. We hypothesize that pUL37x1 and pUL38 use Ca2+ and mTOR signaling to promote the synthesis of PC-VLCFAs required for HCMV replication. We will test this hypothesis by determining the mechanisms by which pUL37x1 and pUL38 promote synthesis of PL-VLCFAs (Aim 1) and defining the PL-VLCFA synthesis enzymes required for HCMV replication and the role of PL-VLCFAs in infection (Aim 2). These studies will determine the mechanisms by which HCMV interacts with the host to create a unique lipid environment advancing our knowledge of HCMV reprogramming of metabolism. Furthermore, these studies will define the biological functions of PC-VLCFAs in HCMV replication and further our understanding of lipids required for HCMV infection. Determining the mechanisms involved in HCMV-induced reprogramming of lipid metabolism and functions of PC-VLCFAs will advance knowledge in HCMV biology needed to identify new targets for treating infection.