HCMV US28 regulation of host cell signaling in viral latency and hematopoiesis

HCMV US28 对病毒潜伏期和造血过程中宿主细胞信号传导的调节

基本信息

批准号：
10216635
负责人：
DANIEL N STREBLOW
金额：
$ 25.42万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216635
关键词：
Affect Allogenic BLT mice Binding Biosensor Bone Marrow Transplantation CCL2 gene CD34 gene CREB1 gene CX3C Chemokines Cell Differentiation process Cell Lineage Cell Maintenance Cell model Cells Characteristics Cues Cytomegalovirus Development Disease EGF Signaling Pathway EGF gene Ensure Epithelial Equilibrium Event Fractalkine Gene Expression Genetic Transcription Goals Graft Rejection Growth Factor Receptors Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Herpesviridae Human Immediate-Early Genes Immune In Vitro Infection Inflammation Inflammatory Ligands Mediating Mediator of activation protein MicroRNAs Modeling Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Mutation Myelogenous Myelosuppression Organ Transplantation PTK2 gene Pathway interactions Population Proteins RANTES Receptor Signaling Recombinant Delta Chemokine Regulation Role Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Solid Stem cell transplant Stimulus Therapeutic Intervention Transcriptional Activation Transplant Recipients Transplant-Related Disorder Transplantation Viral Viral Proteins Virus Virus Latency Virus Replication base beta-Chemokines cell motility chemokine chemokine receptor gene product graft failure humanized mouse in vivo inhibitor/antagonist latency-associated protein macrophage migration monocyte mortality mouse model multiple omics novel therapeutics nuclear factors of activated T-cells peripheral blood prevent programs reactivation from latency receptor expression receptor-mediated signaling response targeted treatment transcriptome sequencing

项目摘要

PROJECT 3 SUMMARY Human cytomegalovirus (HCMV) is a -herpesvirus infecting 44-100% of the population and remains a significant cause of morbidity and mortality in solid organ transplant (SOT) and allogeneic hematopoietic stem cell transplant (SCT) recipients. Infection in SCT patients is often associated with myelosuppression and graft failure due to virus reactivation from latency, but the associated mechanisms are still largely unknown. HCMV encodes multiple latency-associated gene products including the chemokine receptor US28, which binds CC- chemokines as well as the CX3C-chmokine Fractalkine. US28 signals in both ligand-independent and ligand- dependent manners, but the downstream signaling pathways and consequences are unique for each. Importantly, herein we demonstrate that US28 is required for latency and/or reactivation in both in vitro CD34+ hematopoietic progenitor cells (HPCs) as well as in a humanized mouse model. In addition, we show that US28 is sufficient to promote CD34+ HPC differentiation into myeloid lineage cells. Therefore, based upon our exciting new findings, we hypothesize that US28 ligand-independent signaling during latency helps to maintain latency and that ligand-specific signaling promotes CD34+ HPC differentiation into a reactivation/replication competent myeloid lineage cell to ensure virus replication under appropriate conditions including inflammation. US28 signaling may also contribute to other aspects of latency by acting as a biosensor to promote migration towards inflammatory chemokines, and possibly by increasing immediate early gene expression during reactivation. Defining the role of US28 in latency and reactivation, determining how US28 signaling intersects with EGFR signaling, and understanding how US28 signaling influences other HCMV proteins (Projects 1 and 4) and miRNAs (Project 2) expressed during latency and manipulating EGFR signaling (Project 5) are the goals of this proposal. We propose the following specific aims: 1) To determine how US28 signaling in CD34+ HPCs intersects with EGFR signaling pathways using a multi-omics approach; 2) To determine what molecular characteristics of US28 mediate HCMV latency and reactivation using both in vitro CD34+ HPCs and in vivo humanized BLT mouse models; 3) To determine what US28 signaling pathways promote CD34+ HPC hematopoiesis also using both in vitro CD34+ HPC and in vivo huBLT models. Results of this study will generate new virus latency and reactivation paradigms promoting the development of novel therapies to prevent virus reactivation and to treat HCMV-mediated myelosuppression.

项目3摘要人类巨细胞病毒（HCMV）是感染了44-100％人群的疱疹病毒，并且仍然是固体器官移植（SOT）和同种异体造血茎的发病率和死亡率的显着原因细胞移植（SCT）受体。 SCT患者的感染通常与骨髓抑制和移植物有关由于潜伏期引起的病毒重新激活而导致的失败，但相关机制仍然在很大程度上未知。 HCMV 编码多个与延迟相关的基因产物，包括趋化因子受体US28，它结合了CC- 趋化因子以及CX3C-Chmokine Fractalkine。 US28非依赖配体和配体中的信号依赖的举止，但是下游信号通路和后果是独特的。重要的是，我们在此证明US28在体外CD34+中都需要延迟和/或重新激活造血祖细胞（HPC）以及人性化小鼠模型中。此外，我们表明 US28足以将CD34+ HPC分化为髓样谱系细胞。因此，基于我们的令人兴奋的新发现，我们假设延迟期间US28配体的信号传导有助于维护潜伏期和配体特异性信号传导可将CD34+ HPC分化为重新激活/复制有能力的髓样谱系细胞确保在适当的疾病（包括炎症）下复制病毒。 US28信号传导也可能通过充当促进迁移的生物传感器来促进潜伏期的其他方面朝着炎性趋化因子迈进，并且可能是通过立即增加基因表达重新激活。定义US28在延迟和重新激活中的作用，确定US28信号如何相互作用通过EGFR信令，并了解US28信号如何影响其他HCMV蛋白（项目1和 4）和在延迟和操纵EGFR信号（项目5）中表达的miRNA（项目2）是该提议的目标。我们提出以下特定目的：1）确定CD34+中的US28信号如何 HPC使用多词方法与EGFR信号通路相交。 2）确定什么分子使用体外CD34+ HPC和体内的US28介质HCMV潜伏期和重新激活的特征人性化的BLT小鼠模型； 3）确定US28信号通路促进CD34+ HPC 造血还使用体外CD34+ HPC和体内Hublt模型。这项研究的结果将产生新的病毒潜伏期和重新激活范例，促进新疗法的发展防止病毒重新激活并治疗HCMV介导的骨髓抑制。