Control of Human Cytomegalovirus

人类巨细胞病毒的控制

• 批准号: 8762410
• 负责人: JEFFERY L MEIER
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762410
• 关键词: Acute; Antiviral Agents; Antiviral Therapy; Binding; Binding Proteins; Biological; Biology; Boxing; Cell model; Cells; Cessation of life; Code; Cues; Cytomegalovirus; Cytomegalovirus Infections; Data; Dendritic Cells; Development; Disease; Elements; Endothelial Cells; Enhancers; Environment; Epithelial Cells; Fibroblasts; Flow Cytometry; Gene Expression; Gene Expression Regulation; Genome; Goals; Health; Human; Immediate-Early Genes; In Vitro; Infection; Intervention; Investigation; Iowa; Knowledge; Laboratories; Lead; Link; Lytic; Methods; Microscopy; Modeling; Molecular; Myeloid Cells; Neurons; Pathway interactions; Phase; Population; Prevention; Primates; Proteins; Proteomics; Regulation; Regulatory Element; Regulatory Pathway; Research; Resources; Role; Signal Pathway; Signal Transduction; Stimulus; Structure; Supporting Cell; Technology; Testing; Universities; Veterans; Viral; Virus; Virus Latency; base; burden of illness; cell type; drug development; improved; innovation; innovative technologies; latent infection; meetings; nonhuman primate; novel; novel strategies; precursor cell; promoter; tool; transcription factor

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) persistently infects over half of the Veteran population and causes disease and death in a sizeable segment of this population despite advances in antiviral therapy. Novel strategies to mitigate the disease burden resulting from HCMV infection are needed. The HCMV MIE enhancer/promoter serves as the lytic switch for the virus. It is turned on to initiate the viral replicative cycle and turned off during viral latency. Knowledge about the ways in which the HCMV MIE lytic switch is controlled has the potential to inform the development of new therapies to pre-empt viral replication. Our laboratory is at the forefront of investigations into defining the control mechanisms. These early results have led us to hypothesize that the transcriptional regulatory hierarchies and cis-regulatory codes in control of HCMV MIE lytic switch activation differ between cell types in acutely productive and reactivation infections. Preliminary data in human pluripotent N-Tera2 cells (NT2) suggest that HCMV MIE reactivation is best achieved by a combination of different cues and multiple regulatory pathways. There is both a need to further elucidate the cues and regulatory pathways involved and a need to evaluate these findings in a HCMV latency model in dendritic- monocytic cell (D/M) precursors. These results will be the first to elucidate the molecular mechanisms controlling HCMV MIE lytic switch reactivation. Preliminary data in acutely infected permissive fibroblasts reveal a novel regulatory mechanism which functions atypically in the post-immediate-early phase of infection and acts together with another yet unidentified regulatory mechanism. Filling in the gaps in knowledge about action, mechanism, and purpose of this regulatory mechanism is anticipated to shift paradigm in explaining how the MIE enhancer governs HCMV replication. The specific aims of this project are to delineate the differential roles of specific transcription factor pathways and cis-regulatory codes in HCMV MIE lytic switch activation in: 1) acutely infected permissive fibroblast, endothelial, epithelial, and myeloid cells; and 2) quiescently infected NT2 and D/M precursors. The research plan will draw on both innovative approaches and tools. The use of advanced technology and state-of-the-art methods makes feasible the detailing of these pathways at unparalleled depth in diverse cellular settings of biological import. An outstanding research environment and an accomplished research team that interfaces well with the Central Microscopy Research, Proteomics, and Flow Cytometry facilities at the University of Iowa are ideally suited for carrying out this plan. The discovery of viral regulatory mechanisms that can be disrupted to stop HCMV gene expression and replication before it begins potentially provides a new direction in antiviral drug development, with the goal of improving Veterans' health.

描述（由申请人提供）： 尽管抗病毒治疗取得了进展，但人类巨细胞病毒 (HCMV) 持续感染一半以上的退伍军人，并导致相当大一部分人患病和死亡。需要新的策略来减轻 HCMV 感染造成的疾病负担。 HCMV MIE 增强子/启动子充当病毒的裂解开关。它被打开以启动病毒复制周期，并在病毒潜伏期间关闭。了解 HCMV MIE 裂解开关的控制方式有可能为开发新疗法以预防病毒复制提供信息。我们的实验室处于定义控制机制研究的前沿。这些早期结果使我们推测，在急性生产性感染和再激活感染中，控制 HCMV MIE 裂解开关激活的转录调控层次和顺式调控代码在细胞类型之间有所不同。人多能 N-Tera2 细胞 (NT2) 的初步数据表明，HCMV MIE 重新激活最好通过不同线索和多种调控途径的组合来实现。既需要进一步阐明所涉及的线索和调节途径，也需要在树突状单核细胞 (D/M) 前体细胞的 HCMV 潜伏模型中评估这些发现。这些结果将首次阐明控制 HCMV MIE 裂解开关重新激活的分子机制。急性感染的允许成纤维细胞的初步数据揭示了一种新的调节机制，该机制在感染后立即早期阶段发挥非典型作用，并与另一种尚未识别的调节机制一起发挥作用。填补有关该调节机制的作用、机制和目的的知识空白预计将改变解释 MIE 增强子如何控制 HCMV 复制的范式。该项目的具体目标是描述特定转录因子途径和顺式调节密码在 HCMV MIE 裂解开关激活中的不同作用：1) 急性感染的允许成纤维细胞、内皮细胞、上皮细胞和骨髓细胞； 2) 静态感染的 NT2 和 D/M 前体。该研究计划将利用创新方法和工具。先进技术和最先进方法的使用使得在生物输入的不同细胞环境中以无与伦比的深度详细描述这些途径成为可能。爱荷华大学卓越的研究环境和优秀的研究团队与中央显微镜研究、蛋白质组学和流式细胞术设施良好配合，非常适合实施这一计划。病毒调控机制的发现可以在 HCMV 基因表达和复制开始之前被破坏，从而阻止其发生，这可能为抗病毒药物开发提供新方向，其目标是改善退伍军人的健康。

项目成果

The human cytomegalovirus UL133-138 gene locus attenuates the lytic viral cycle in fibroblasts.

• DOI: 10.1371/journal.pone.0120946
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dutta N;Lashmit P;Yuan J;Meier J;Stinski MF
• 通讯作者: Stinski MF

Mitogen and stress activated kinases act co-operatively with CREB during the induction of human cytomegalovirus immediate-early gene expression from latency.

• DOI: 10.1371/journal.ppat.1004195
• 发表时间: 2014-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Kew VG;Yuan J;Meier J;Reeves MB
• 通讯作者: Reeves MB

Breaking human cytomegalovirus major immediate-early gene silence by vasoactive intestinal peptide stimulation of the protein kinase A-CREB-TORC2 signaling cascade in human pluripotent embryonal NTera2 cells.

通过血管活性肠肽刺激人多能胚胎 NTera2 细胞中的蛋白激酶 A-CREB-TORC2 信号级联，打破人巨细胞病毒主要立即早期基因沉默。

• DOI: 10.1128/jvi.00061-09
• 发表时间: 2009
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Yuan,Jinxiang;Liu,Xiaoqiu;Wu,AllenW;McGonagill,PatrickW;Keller,MichaelJ;Galle,CourtneyS;Meier,JefferyL
• 通讯作者: Meier,JefferyL