Manipulation of host factors that promote HCMV latency

操纵促进 HCMV 潜伏期的宿主因素

• 批准号: 10573191
• 负责人: CHRISTINE M O'CONNOR
• 金额: $ 47.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573191
• 关键词: Adult; Affect; Antiviral Therapy; Attenuated; Binding; Biological; Biological Models; Biological Process; Biology; Cells; Child; Chromatin; Complex; Coupled; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; EPHA2 gene; Early Promoters; Fetal Development; Foundations; Future; G-Protein-Coupled Receptors; Gene Silencing; Genes; Genetic Transcription; Goals; Hematopoietic; Hematopoietic stem cells; Herpesviridae; Human; Immune system; Immunocompetent; Immunocompromised Host; Immunologics; In Vitro; Individual; Infection; Integration Host Factors; Knowledge; Life; Lytic; MAP Kinase Gene; MEKs; Maintenance; Mediating; Modeling; Molecular; Morbidity - disease rate; Outcome; Pathogenesis; Pathway interactions; Persons; Population; Primary Infection; Production; Recombinants; Repression; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Supporting Cell; Testing; Transcription Factor AP-1; United States; Up-Regulation; Viral; Virus; Virus Activation; Virus Latency; Work; YY1 Transcription Factor; attenuation; cellular targeting; experimental study; improved; latent infection; mortality; mutant; novel; novel strategies; novel therapeutics; organ transplant recipient; pathogen; prevent; promoter; reactivation from latency; recruit; transcription factor

PROJECT SUMMARY/ABSTRACT – O’CONNOR, CHRISTINE M. Human cytomegalovirus (HCMV) is a wide-spread pathogen, infecting the majority of the population in the United States. This virus poses a significant threat to developing fetuses as well as to children and adults who lack a competent immune system, often causing severe disease and mortality. Once individuals acquire an HCMV infection, the virus remains with the host for life, in a latent or quiescent state in the hematopoietic compartment. During times of severe immunological stress, the virus reactivates to its active state, allowing for dissemination and subsequent disease. With the exception of the immuno-naïve and sero-negative organ transplant recipients, primary infection with HCMV rarely causes disease, but rather it is reactivation that leads to significant complications. Thus, to prevent HCMV-associated disease, we must gain a complete understanding of viral latency and reactivation. One of a handful of genes encoded during latency is one of the four viral G protein-coupled receptors (GPCRs), US28. We have shown previously that US28 is required for the establishment and maintenance latency and that US28-mediated signaling contributes to these effects. We have also found that US28 modulates the expression of specific cellular targets that regulate the Major Immediate Early Promoter (MIEP), a master regulator in the latent-to-lytic switch. Therefore, we hypothesize that US28 modulates specific host signaling pathways to regulate transcriptional silencing of the MIEP to facilitate HCMV latency. To explore this hypothesis, we will take advantage novel approaches coupled with our arsenal of US28- specific recombinants, as well as both in vitro and ex vivo latency model systems. In Aim 1, we will define mechanisms underlying US28-mediated attenuation of AP-1 transcription factor binding to the MIEP during latency by examining the upstream signaling pathways that regulate AP-1. In Aim 2, we will determine the factors that recruit YY1 to the MIEP during latency by assessing US28-regulated signaling pathways and factors that promote the binding of this repressive transcription factor. In sum, the experiments proposed herein will lead to a greater understanding of US28’s biological functions during latency and will lay the foundation for future studies to develop novel therapeutics specifically targeting the latent reservoir of HCMV infection.

项目概要/摘要-奥康纳，克莉丝汀M. 人巨细胞病毒（HCMV）是一种广泛传播的病原体，感染大多数人， 美国的人口。这种病毒对发展中国家的 胎儿以及缺乏有效免疫系统的儿童和成人， 导致严重的疾病和死亡。一旦个体获得HCMV感染， 病毒与宿主终生共存，在造血系统中处于潜伏或静止状态。 车厢在严重的免疫应激期间，病毒重新激活， 活跃状态，允许传播和随后的疾病。但不包括 免疫初治和血清阴性的器官移植受者，原发性感染 HCMV很少引起疾病，但它是重新激活，导致显着 并发症因此，为了预防HCMV相关疾病，我们必须获得一个完整的 了解病毒潜伏期和再激活。少数几个基因之一 在潜伏期期间，是四种病毒G蛋白偶联受体（GPCR）之一，US 28。我们 我之前已经表明，建立和维护 潜伏期和US 28介导的信号传导有助于这些作用。我们还 发现US 28调节特定细胞靶点的表达，这些靶点调节 主要立即早期启动子（MIEP），潜伏-裂解转换的主要调节因子。 因此，我们假设US 28调节特定的宿主信号通路， 调节MIEP的转录沉默以促进HCMV潜伏。探索这个 假设，我们将利用新的方法，加上我们的武器库US 28- 特异性重组体，以及体外和离体潜伏期模型系统。在Aim中 1，我们将定义US 28介导的AP-1衰减的潜在机制 转录因子结合的MIEP在潜伏期通过检查上游 调节AP-1的信号通路。在目标2中，我们将确定招募的因素 通过评估US 28调节的信号通路， 促进这种抑制性转录因子结合的因子。总之， 本文提出的实验将有助于更好地了解US 28的生物学特性 在潜伏期的功能，并将奠定基础，为未来的研究，开发新的 特异性靶向HCMV感染的潜伏储库的治疗剂。