Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism

人类巨细胞病毒重编程脂质代谢的机制

• 批准号: 10438866
• 负责人: John Gerard Purdy
• 金额: $ 37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438866
• 关键词: Address; Binding; Biochemical Pathway; Biological; Biological Process; Biology; CRISPR/Cas technology; Cells; Cessation of life; Cytomegalovirus; Data; Dietary Intervention; Disease; Ensure; Environment; Enzymes; FRAP1 gene; Foundations; Glycoproteins; Goals; Herpesviridae; Human; Immunocompromised Host; Infection; Integration Host Factors; Knock-out; Knowledge; Lecithin; Life; Lipids; Membrane; Metabolic; Metabolism; Modeling; Molecular; Newborn Infant; Phospholipids; Positioning Attribute; Proteins; Public Health; Research; Role; Signal Pathway; Signal Transduction; Stress; Tail; Testing; Very Long Chain Fatty Acid; Viral; Virus; Virus Replication; Work; biological adaptation to stress; disability; experience; lipid biosynthesis; lipid metabolism; lipidome; lipidomics; mutant; novel; receptor; response; small molecule; virus host interaction

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.

项目概要 人类巨细胞病毒 (HCMV) 是一种疱疹病毒，可导致人类疾病和死亡。 免疫功能低下，是先天性残疾的主要原因。 HCMV 复制需要脂质。 由于 HCMV 不编码代谢网络，因此病毒复制依赖于宿主脂质代谢。 然而，人们对 HCMV 如何重新编程宿主代谢以确保病毒所需的脂质知之甚少。 进行了复制。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 HCMV 复制至关重要。最近，我们发现HCMV感染导致脂质增加 合成和脂质丰度的增加。在这里，我们证明 HCMV 感染诱导合成 至少 20 种以前未描述过的受感染细胞特有的脂质。这些独特的脂质大部分是磷脂 具有极长链脂肪酸尾（PL-VLCFA）。本申请中讨论的 PL-VLCFA 是 在我们的工作之外，HCMV 生物学总体上没有得到充分研究，也没有得到研究。虽然 FA 尾部较短 经过充分研究，我们对具有与 HCMV 中观察到的一样长的 VLCFA 尾部的脂质知之甚少 感染，包括它们在生物膜中的表现。这背后的分子机制 HCMV 诱导的宿主脂质组扩增以及新产生的脂质的功能作用 很大程度上不为人知。 我们发现 HCMV pUL37x1 和 pUL38 蛋白促进 PL-VLCFA 合成，奠定了 为了解 HCMV 重新编程脂质合成的机制奠定了基础。 pUL37x1 和 pUL38 分别诱导 Ca2+ 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有助于 HCMV 脂质重塑。我们假设 pUL37x1 和 pUL38 使用 Ca2+ 和 mTOR 信号传导促进 PC-VLCFA 的合成 HCMV 复制。我们将通过确定 pUL37x1 和 pUL38 的机制来检验这一假设。 促进 PL-VLCFA 的合成（目标 1）并确定 HCMV 所需的 PL-VLCFA 合成酶 PL-VLCFA 的复制和在感染中的作用（目标 2）。这些研究将通过以下方式确定其机制： HCMV 与宿主相互作用，创造独特的脂质环境，增进我们对 HCMV 的了解 新陈代谢的重新编程。此外，这些研究将定义 PC-VLCFA 的生物学功能 HCMV 复制并进一步了解 HCMV 感染所需的脂质。确定 涉及 HCMV 诱导的脂质代谢重编程和 PC-VLCFA 功能的机制将 确定治疗感染的新靶点需要先进的 HCMV 生物学知识。