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

人类巨细胞病毒或称巨细胞病毒是已知的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感染。一旦人巨细胞病毒进入人体，它就会终生停留在那里，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，也不会产生病毒。虽然人巨细胞病毒可能在人体的几个部位潜伏，但“髓系”型的血液和骨髓细胞是人巨细胞病毒潜伏期最知名的部位。大多数被感染的健康成人和儿童几乎没有体征或症状，而且不会受到HCMV的长期影响。然而，面临风险的人包括那些免疫系统减弱的人，包括接受移植、接受癌症化疗或艾滋病毒呈阳性的个人。众所周知，在这些人中，人巨细胞病毒可以导致危及生命的疾病，影响到多个器官。然而，人类巨细胞病毒也是世界范围内先天性(出生时存在的)感染的主要原因这一事实，以及这种病毒作为儿童听力损失和脑部疾病最常见的原因所产生的社会经济影响，还没有得到足够的重视。在英国，每天有两到三名婴儿受到巨细胞病毒的损害(每年近1000名婴儿)。事实上，人类巨细胞病毒导致的出生缺陷和儿童死亡比唐氏综合症、弓形体病或李斯特菌病更多，而且比寨卡病毒更令人担忧。然而，先天性巨细胞病毒在医护人员和公众中缺乏认识。此外，由于所有可用的药物都有危险的副作用，目前还没有针对这种病毒的疫苗，也没有批准的先天性感染治疗方法。因此，迫切需要确定新的分子靶点和更好的药物来治疗hCMV。虽然HCMV在高危人群首次感染时可能会引起严重症状，但当病毒在潜伏感染的个人中重新激活时，疾病通常会接踵而至。从潜伏期重新激活被认为是一个循序渐进的过程，最终导致病毒基因的全球激活和传染性病毒的产生。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。我们之前的大部分研究都集中在一种名为立即早期1或IE1的巨细胞病毒蛋白上。IE1被认为是在HCMV重新激活过程中产生的第一种病毒蛋白，因此有望在这一过程中发挥重要作用。在初步实验的基础上，我们认为IE1至少通过两种分子机制在HCMV的重新激活中发挥关键作用，这两种机制分别涉及信号转导和转录激活因子(STAT)家族的宿主蛋白和核小体，它们分别是染色质的基本构件。我们将使用最先进的技术，使用受感染的人髓系细胞作为模型来阐明IE1是如何确切地调制与STAT蛋白相连的分子通路来重新激活病毒生产的。同样，我们将确定IE1介导的病毒基因重新激活的潜在的基于染色质的“表观遗传”机制。最后，我们将评估针对与IE1介导的重新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者的潜力。这项工作的结果将极大地改善我们对HCMV如何从潜伏期重新激活从而导致疾病的有限的分子理解。他们还将揭示抗击这种重要但有些被忽视的人类病原体的新策略。

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.