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: 10629163
• 负责人: DANIEL N STREBLOW
• 金额: $ 257.08万
• 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/10629163
• 关键词: Address; Apoptosis; Bioinformatics; Biological Assay; Biometry; Bone Marrow; CD34 gene; Cell Differentiation process; Cells; Clinical; Collaborations; Complex; Cytomegalovirus; Cytomegalovirus Infections; Environment; Epidermal Growth Factor Receptor; Event; Exhibits; Funding; Goals; Growth Factor; Growth Factor Receptors; Guanosine Triphosphate Phosphohydrolases; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Knowledge; Life Cycle Stages; Ligand Binding; Ligands; Link; MEKs; Macrophage; Maintenance; Mediator; MicroRNAs; Molecular; Morbidity - disease rate; Myeloid Cells; Myelopoiesis; Myelosuppression; Organ Transplantation; Pathway interactions; Patients; Process; Production; Productivity; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Regulation; Research Design; Research Project Grants; Role; STAT1 gene; Services; Shapes; Signal Induction; Signal Pathway; Signal Transduction; Solid; Stem cell transplant; Testing; Time; Tissues; Transplant Recipients; Viral; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; Work; chemokine; cytokine; gene interaction; humanized mouse; insight; monocyte; mortality; mutant; novel virus; permissiveness; programs; reactivation from latency; response; rho GTP-Binding Proteins; stem cell homeostasis; stem cell proliferation; stem cells; synergism; 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）是造血干细胞发病和死亡的重要原因 移植（HSCT）患者经常表现出与病毒感染相关的骨髓抑制。 CD34+ 造血祖细胞 (HPC) 是潜在 HCMV 的关键储存库，在细胞因子和生长过程中 因子信号分化为单核细胞，进一步分化为巨噬细胞，激活 组织中的传染性病毒。 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也至关重要 和造血作用。在过去的 3.5 年里，我们已经确定了受以下因素调节的关键 EGFR 信号通路： UL138、UL136、UL135、US28、UL7、UL8 和多种 HCMV miRNA，对于维持潜伏期或 诱导病毒重新激活。大多数这些途径与 CD34+ HPC 增殖密切相关 维持骨髓生态位中的祖细胞以及骨髓生成。我们已经证明 多个 HCMV miRNA 与 HCMV 蛋白协同或拮抗地共同调节这些 潜伏或病毒重新激活所需的信号传导途径。此外，我们观察到 UL138 是 与参与 STAT1 信号转导的蛋白质相关，并且 HCMV miRNA 靶向其中一些因子。我们 假设 UL138-WDR48-USP1 和 -USP12 与 US28 和 HCMV miRNA 相互作用 调节 STAT1 和 AKT 反应以抑制病毒复制的潜伏期。我们还表明，US28 趋化因子诱导的信号传导调节潜伏期或重新激活，并且是配体特异性的。此外，我们还有 观察到 RhoA 的 US28 激活受到 HCMV miRNA 以及 UL8 信号传导的高度调节 非经典 Wnt 通路。我们假设 MEK/ERK 信号传导对于维持延迟至关重要 RhoA 途径的激活是重新激活所必需的。 目前的HCMV PPG主要集中在UL138、UL136、UL135、US28、UL7和病毒的鉴定上。 miRNA EGFR 信号传导靶标，拟议的更新将重点关注不同 HCMV 基因如何与 相互调节这些途径以及它们如何控制病毒的生命周期。信号的复杂性 全面解决病毒潜伏期和造血问题的事件和方法只能是 通过PPG机制下的协作努力来实现。因此我们提出了五种高度集成的 研究项目（项目1：UL133/8在病毒潜伏和重新激活过程中对宿主细胞信号传导的调节；项目2： 病毒潜伏期和再激活过程中宿主细胞信号转导的 miRNA 调节；项目3：US28对宿主细胞的调控 病毒潜伏期和重新激活的信号传导；项目 4：UL7-8 在病毒潜伏期和宿主细胞信号传导中的调节 重新激活；项目5：病毒再激活中单核细胞/巨噬细胞宿主细胞信号传导的HCMV调节），两个 为这些项目提供服务的科学核心（人源化小鼠核心；生物统计学和生物信息学核心），以及 监督和协调整个计划的行政核心。

项目成果

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection.

E3 泛素连接酶 SIAH1 在登革热病毒感染期间以 MyD88 为蛋白酶体降解目标。

• 发表时间: 2020
• 作者: Murphy Schafer, Ashleigh R;Smith, Jessica L;Pryke, Kara M;DeFilippis, Victor R;Hirsch, Alec J
• 通讯作者: Hirsch, Alec J

OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism.

OR14I1 是人巨细胞病毒五聚体复合物的受体，定义了病毒上皮细胞的趋向性。

• 发表时间: 2019-04-02
• 影响因子: 11.1
• 作者: E, Xiaofei;Meraner, Paul;Lu, Ping;Perreira, Jill M;Aker, Aaron M;McDougall, William M;Zhuge, Ronghua;Chan, Gary C;Gerstein, Rachel M;Caposio, Patrizia;Yurochko, Andrew D;Brass, Abraham L;Kowalik, Timothy F
• 通讯作者: Kowalik, Timothy F

HCMV miRNA Targets Reveal Important Cellular Pathways for Viral Replication, Latency, and Reactivation.

HCMV miRNA 靶标揭示了病毒复制、潜伏和重新激活的重要细胞途径。

• 发表时间: 2018-10-22
• 作者: Diggins, Nicole L;Hancock, Meaghan H
• 通讯作者: Hancock, Meaghan H

Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation.

分子决定因素和人类巨细胞病毒潜伏期和再激活的调节。

• 发表时间: 2018-08-20
• 作者: Collins;Buehler, Jason;Peppenelli, Megan;Goodrum, Felicia
• 通讯作者: Goodrum, Felicia

Human Cytomegalovirus UL7, miR-US5-1, and miR-UL112-3p Inactivation of FOXO3a Protects CD34+ Hematopoietic Progenitor Cells from Apoptosis.

人巨细胞病毒 UL7、miR-US5-1 和 miR-UL112-3p FOXO3a 失活可保护 CD34 造血祖细胞免于凋亡。

• 发表时间: 2021
• 影响因子: 4.8
• 作者: Hancock, Meaghan H;Crawford, Lindsey B;Perez, Wilma;Struthers, Hillary M;Mitchell, Jennifer;Caposio, Patrizia
• 通讯作者: Caposio, Patrizia