Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation

人类巨细胞病毒对宿主造血祖细胞信号通路的失调调节潜伏期和重新激活

• 批准号: 10327944
• 负责人: JAY A NELSON
• 金额: $ 260.58万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327944
• 关键词: Address; Apoptosis; Bioinformatics; Biological Assay; Biometry; Bone Marrow; CD34 gene; Cell Differentiation process; Cells; Clinical; Collaborations; Complex; Cytomegalovirus; Environment; Epidermal Growth Factor Receptor; Event; Exhibits; Funding; Genes; Goals; Growth Factor; Growth Factor Receptors; Guanosine Triphosphate Phosphohydrolases; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Infection; Knowledge; Life Cycle Stages; Ligand Binding; Ligands; Link; MEKs; Maintenance; Mediator of activation protein; MicroRNAs; Molecular; Morbidity - disease rate; Myeloid Cells; Myelopoiesis; Myelosuppression; Organ Transplantation; Pathway interactions; Patients; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Regulation; Research Design; Research Project Grants; Role; STAT1 gene; Services; Signal Pathway; Signal Transduction; Solid; Testing; Time; Tissues; Transplant Recipients; Viral; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; Work; chemokine; cytokine; humanized mouse; insight; macrophage; monocyte; mortality; mutant; novel virus; programs; reactivation from latency; response; rho GTP-Binding Proteins; stem cell homeostasis; stem cell proliferation; stem cells; transcriptome; virus host interaction

SUMMARY - OVERALL Human Cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients who often exhibit myelosuppression associated with virus infection. CD34+ Hematopoietic Progenitor Cells (HPCs) are a critical reservoir of latent HCMV that upon cytokine and growth factor signals differentiate into monocytes that further differentiate into macrophages activating production of infectious virus in tissues. Epidermal Growth Factor Receptor (EGFR) signaling pathways in CD34+ HPCs are critical not only for determining HCMV latency and reactivation but also for regulating progenitor cell homeostasis and hematopoiesis. Over the past 3.5 years we have identified critical EGFR signaling pathways regulated by UL138, UL136, UL135, US28, UL7, UL8, and multiple HCMV miRNAs that are important to maintain latency or induce viral reactivation. Most of these pathways are integrally linked with CD34+ HPC proliferation for maintenance of the progenitor cell in the bone marrow niche as well as myelopoiesis. We have shown that multiple HCMV miRNAs synergistically or antagonistically work together with HCMV proteins to regulate these signaling pathways necessary for latency or viral reactivation. In addition, we have observed that UL138 is associated with proteins involved in STAT1 signaling and that HCMV miRNAs target some of these factors. We hypothesize that UL138-WDR48-USP1 and -USP12 interactions along with US28 and the HCMV miRNAs regulate a STAT1 and AKT response to suppress virus replication for latency. We have also shown that US28 signaling induced by chemokines regulate latency or reactivation and is ligand specific. Additionally, we have observed that US28 activation of RhoA is highly regulated by HCMV miRNAs as well as UL8 signaling through the non-canonical Wnt pathway. We hypothesize that MEK/ERK signaling is essential to maintain latency while activation of the RhoA pathway is necessary for reactivation. While the current HCMV PPG has focused on identification of UL138, UL136, UL135, US28, UL7, and viral miRNA EGFR signaling targets, the proposed renewal will focus on how the different HCMV genes interact with one another to regulate these pathways and how they control the virus life cycle. The complexity of signaling events and approaches to comprehensively address questions on viral latency and hematopoiesis can only be achieved through a collaborative effort under a PPG mechanism. Therefore we propose five highly integrated research projects (Project 1: UL133/8 regulation of host cell signaling in viral latency and reactivation; Project 2: miRNA regulation of host cell signaling in viral latency and reactivation; Project 3: US28 regulation of host cell signaling in viral latency and reactivation; Project 4: UL7-8 regulation of host cell signaling in viral latency and reactivation; Project 5: HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation), two scientific cores (Humanized Mouse Core; Biostatistics and Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire program.

摘要 - 总体 人类巨细胞病毒（HCMV）是造血干细胞发病率和死亡率的重要原因 经常表现出与病毒感染相关的骨髓抑制的移植（HSCT）患者。 CD34+ 造血祖细胞（HPC）是潜在HCMV的关键储层，它在细胞因子和生长时 因子信号分化为单核细胞，从而进一步分化为巨噬细胞激活的产生 组织中的传染病。 CD34+ HPC中的表皮生长因子受体（EGFR）信号通路是 不仅对于确定HCMV潜伏期和重新激活至关重要，而且对于调节祖细胞稳态 和造血。在过去的3。5年中 UL138，UL136，UL135，US28，UL7，UL8和多个HCMV miRNA对于保持潜伏期或 诱导病毒重新激活。这些途径中的大多数与CD34+ HPC增殖的整合 维持骨髓细分市场中的祖细胞以及骨髓菌。我们已经表明 多个HCMV miRNA在协同或拮抗的上与HCMV蛋白一起进行调节以调节这些 延迟或病毒重新激活所需的信号通路。此外，我们观察到UL138是 与参与STAT1信号传导的蛋白质以及HCMV miRNA有关的蛋白质针对其中一些因素。我们 假设UL138-WDR48-USP1和-USP12与US28和HCMV miRNA的相互作用 调节STAT1和AKT响应以抑制病毒复制的潜伏期。我们还证明了US28 趋化因子诱导的信号传导调节潜伏期或重新激活，并且是特定于配体的。另外，我们还有 观察到RhoA的US28激活受HCMV miRNA以及通过UL8信号的高度调节 非典型的WNT途径。我们假设MEK/ERK信号对于保持潜伏期至关重要 RhoA途径的激活是重新激活所必需的。 虽然当前的HCMV PPG专注于识别UL138，UL136，UL135，US28，UL7和病毒 miRNA EGFR信号转导目标，提出的更新将集中于不同的HCMV基因如何与 一个彼此调节这些途径及其如何控制病毒生命周期的方法。信号传导的复杂性 全面解决有关病毒潜伏期和造血的问题的事件和方法只能是 通过PPG机制的协作努力实现。因此，我们提出了五个高度整合的 研究项目（项目1：UL133/8在病毒潜伏和重新激活中对宿主细胞信号的调节；项目2： 病毒潜伏期和重新激活中宿主细胞信号传导的miRNA调节；项目3：US28主机单元的调节 病毒潜伏期和重新激活中的信号传导；项目4：UL7-8病毒潜伏期中宿主细胞信号的调节 重新激活；项目5：病毒重新激活中单核细胞/巨噬细胞宿主细胞信号传导的HCMV调节），两个 科学核心（人性化的小鼠核心；生物统计学和生物信息学核心）为这些项目提供服务，并 管理核心，以监督和协调整个程序。