Role of the Human Cytomegalovirus Major Immediate-Early 1 Protein in Viral Reactivation from Latency

人类巨细胞病毒主要立即早期 1 蛋白在病毒从潜伏期重新激活中的作用

• 批准号: MR/P022146/1
• 负责人: Michael Nevels
• 金额: $ 52.31万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP022146%2F1
• 关键词: Role; Human; Cytomegalovirus; Major; Immediate

Human cytomegalovirus or hCMV is one of eight herpesviruses that are known to infect people. This virus is very common, infecting one out of two persons in the UK. Once hCMV is in a person's body it stays there for life, usually in a dormant state referred to as "latency". In latency, few viral genes are active and no virus is produced. Although hCMV likely remains latent in several places of the human body, blood and bone marrow cells of the "myeloid" type are the best known sites of hCMV latency. Most healthy adults and children who become infected will have few signs or symptoms and no long-term effects from hCMV. However, people at risk include those with weakened immune systems including individuals who receive transplants, undergo cancer chemotherapy or are positive for HIV. It is well established that in these people, hCMV can cause life-threatening disease affecting multiple organs. However, the fact that hCMV is also the leading cause of congenital (present at birth) infections worldwide is less appreciated, and so is the socioeconomic impact of this virus as the most common cause of childhood hearing loss and brain disorders. Two to three babies are damaged by hCMV every day (almost 1,000 babies every year) in the UK. In fact, hCMV causes more birth defects and childhood deaths than Down's syndrome, toxoplasmosis or listeriosis and is a greater global health concern than the Zika virus. Yet, congenital hCMV lacks awareness among health care workers and the public. Furthermore, no vaccine for this virus is available and no approved treatment for congenital infection exists, since all available drugs have dangerous side effects. Consequently, there is an urgent need to identify new molecular targets and better drugs for hCMV.Although hCMV may cause serious symptoms upon initial infection of people at risk, disease more typically ensues when the virus "reactivates" in latently infected individuals. Reactivation from latency is considered to be a stepwise process that ultimately results in the global activation of viral genes and production of infectious virus. How hCMV reactivates from latency is far from clear, especially at the molecular level. Much of our previous research has centred on an hCMV protein known as immediate-early 1 or IE1. IE1 is believed to be the very first viral protein produced during hCMV reactivation and is therefore expected to have an important role in this process. Based on preliminary experiments, we propose that IE1 serves as a key viral factor in hCMV reactivation via at least two molecular mechanisms involving host proteins of the signal transducer and activator of transcription (STAT) family and nucleosomes, the basic building blocks of chromatin, respectively. We will employ state-of-the-art technology using infected human myeloid cells as a model to elucidate how exactly IE1 modulates molecular pathways linked to STAT proteins to reactivate virus production. Likewise, we will identify chromatin-based "epigenetic" mechanisms underlying IE1-mediated reactivation of viral genes. Finally, we will evaluate agents targeting the molecular events linked to IE1-mediated reactivation for their antiviral capacity and potential to serve as candidates for drug development. The results from this work will considerably improve our limited molecular understanding of how hCMV reactivates from latency to cause disease. They will also reveal new strategies to combat this important, but somewhat neglected, human pathogen.

人类巨细胞病毒或hCMV是已知感染人类的八种疱疹病毒之一。这种病毒非常常见，在英国每两个人中就有一个人感染。一旦hCMV在一个人的身体里，它会终生停留在那里，通常处于一种被称为“潜伏期”的休眠状态。在潜伏期，很少有病毒基因是活跃的，没有病毒产生。虽然hCMV可能在人体的几个地方保持潜伏，但“髓样”类型的血液和骨髓细胞是hCMV潜伏的最佳已知部位。大多数健康的成年人和儿童谁成为感染将有很少的迹象或症状，并没有长期的影响，从hCMV。然而，处于风险中的人包括免疫系统较弱的人，包括接受移植、接受癌症化疗或艾滋病毒阳性的人。在这些人中，hCMV可以引起危及生命的疾病，影响多个器官。然而，hCMV也是全球先天性（出生时就存在）感染的主要原因这一事实却鲜为人知，这种病毒作为儿童听力损失和脑部疾病最常见原因的社会经济影响也不太为人所知。在英国，每天有两到三个婴儿受到hCMV的损害（每年近1,000个婴儿）。事实上，hCMV比唐氏综合征，弓形虫病或梅毒导致更多的出生缺陷和儿童死亡，并且比寨卡病毒更严重的全球健康问题。然而，先天性hCMV缺乏卫生保健工作者和公众的认识。此外，没有针对这种病毒的疫苗，也没有经批准的先天性感染治疗方法，因为所有现有药物都有危险的副作用。因此，迫切需要确定新的分子靶点和更好的药物hCMV。虽然hCMV可能会导致严重的症状后，首次感染的人处于危险之中，疾病更典型的发作时，病毒“重新激活”在潜伏感染的个人。潜伏期的再激活被认为是一个逐步的过程，最终导致病毒基因的全面激活和感染性病毒的产生。hCMV如何从潜伏期重新激活还远不清楚，特别是在分子水平上。我们以前的大部分研究都集中在一种称为立即早期1或IE 1的hCMV蛋白上。IE 1被认为是hCMV再活化过程中产生的第一个病毒蛋白，因此预计在此过程中具有重要作用。基于初步的实验，我们建议，IE 1作为一个关键的病毒因子在hCMV再激活通过至少两个分子机制，涉及宿主蛋白的信号转导和转录激活因子（STAT）家族和核小体，染色质的基本组成部分，分别。我们将采用最先进的技术，使用受感染的人骨髓细胞作为模型，以阐明IE 1如何确切地调节与STAT蛋白质相关的分子途径，以重新激活病毒的产生。同样，我们将确定基于染色质的“表观遗传”机制IE 1介导的病毒基因的再激活。最后，我们将评估针对与IE 1介导的再激活相关的分子事件的药物的抗病毒能力和作为药物开发候选药物的潜力。这项工作的结果将大大提高我们对hCMV如何从潜伏期重新激活导致疾病的有限分子理解。他们还将揭示对抗这种重要但有点被忽视的人类病原体的新策略。

项目成果

Revisiting the role of PML protein targeting and disruption of PML bodies in human cytomegalovirus infection

重新审视 PML 蛋白靶向和 PML 体破坏在人类巨细胞病毒感染中的作用

• DOI: 10.1099/acmi.ac2020.po0734
• 发表时间: 2020
• 期刊: Access Microbiology
• 作者: Paulus C

The Human Cytomegalovirus IE1 Protein Employs STAT2/3- and Nucleosome-Dependent Mechanisms to Mediate Viral Reactivation from Latency

人类巨细胞病毒 IE1 蛋白利用 STAT2/3 和核小体依赖性机制介导病毒从潜伏期重新激活

• 发表时间: 2017
• 作者: Paulus C

Role of the Immediate-early 1 Protein In Human Cytomegalovirus Infection of Myeloid Cells

立即早期1蛋白在人巨细胞病毒感染骨髓细胞中的作用

• 作者: Mark McNeil

Human Cytomegalovirus Immediate-Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus

• DOI: 10.1101/308171
• 发表时间: 2018-04
• 期刊: bioRxiv
• 作者: Cong-Cong Wu-Cong;Xuan Jiang;Xian-Zhang Wang;Xi-Juan Liu;Xiao-Jun Li;Bo Yang;Hanqing Ye;Thomas Harwardt-Tho