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HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation

HCMV 对病毒再激活中单核细胞/巨噬细胞宿主细胞信号传导的调节

基本信息

批准号：
10629186
负责人：
ANDREW D YUROCHKO
金额：
$ 38.16万
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 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629186
关键词：
Address Animal Model Biological Biology CD34 gene Cell Differentiation process Cell model Cells Chemicals Critical Pathways Cytomegalovirus Cytomegalovirus Infections Data Disease Environment Epidermal Growth Factor Receptor Event Experimental Designs Failure Funding Gene Mutation Genetic Transcription Goals Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Infection Knowledge Laboratories Link Macrophage MicroRNAs Modification Molecular Profiling Morbidity - disease rate Multiomic Data Myelogenous Myeloid Cells Organ Transplantation Pathway interactions Phenotype Play Prevention Process Productivity Regulation Role SRC gene Signal Induction Signal Pathway Signal Transduction Site Solid Testing Time Tissues Translating Transplant Recipients Viral Viral Genes Virion Virus Virus Replication Work arm cell type clinically relevant design directed differentiation gene product humanized mouse immune checkpoint blockade improved outcome in vivo inhibitor insight knock-down latent infection latent virus activation monocyte mortality mouse model multiple omics mutant novel pathogen permissiveness prevent programs reactivation from latency response small hairpin RNA therapeutic target

项目摘要

SUMMARY – PROJECT 5 Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality after hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) due to reactivation or a new infection in these transplant recipients. Our combined PPG laboratories have shown that HCMV infection of CD34+ hematopoietic progenitor cells (HPCs) the site of HCMV latency and subsequent reactivation alters hematopoietic events to favor HPC differentiation towards the myeloid lineage. To fully understand HCMV reactivation process, we need not only understand the process of how reactivating virus in CD34+ HPC directs differentiation towards the myeloid lineage, but also mechanistically how HCMV reactivation in monocytes directs signaling to promote differentiation towards productive macrophages. Through our collaborative program, we have identified viral genes (e.g., UL135, US28, UL7/8) and miRNAs (e.g. miR-US22) that are required for reactivation. Furthermore, through the use of deletion mutant viruses that fail to reactivate, we have identified the existence of blockades to HCMV reactivation that are associated with differentiation into macrophages. The signaling events important for reactivation of latent virus in tissue macrophages remains poorly understood. We suggest temporally unique roles for UL135, US28 and UL7/8 and a unique intersection of these gene products with HCMV miRNAs expressed during latency in usurping the signaling necessary to promote reactivation in this essential cell type. We hypothesize distinct signaling events in monocyte to macrophage differentiation relieve blockades to reactivation and these reactivation events are specifically driven by modifications to cellular signaling by the combined effort of these viral factors. To test our hypothesis, we propose the following aims. Specific Aim 1. Defining signaling networks for HCMV latency and reactivation in monocytes and macrophages. We hypothesize that functionally distinct host cell responses in monocyte-to-macrophage differentiation are essential for reactivation. Specific Aim 2. Determine checkpoint blockades for viruses that fail to reactivate. We hypothesize that a failure in specific cellular signaling reprogramming during reactivation will result in a cell that phenotypically is unable to support viral replication. Specific Aim 3. Define the signaling nodes modulated by infection for reactivation in monocytes/macrophages. We hypothesize that the EGFR and RhoA signaling pathways are critical for HCMV latency and reactivation in macrophages. IMPACT: These proposed aims will allow us to gain greater insight and as we integrate our collective work, we hope to translate the results into novel molecular signatures designed to improve the outcome of an infection that remains a significant problem in transplant recipients.

摘要 – 项目 5 人类巨细胞病毒（HCMV）是造血后发病和死亡的重要原因由于重新激活或新感染而导致的干细胞移植（HSCT）和实体器官移植（SOT）移植受者。我们的联合 PPG 实验室表明，CD34+ 造血系统的 HCMV 感染祖细胞 (HPC) 是 HCMV 潜伏期和随后重新激活的部位，会改变造血事件有利于 HPC 向骨髓谱系分化。为了充分了解 HCMV 重新激活过程，我们需要不仅了解在 CD34+ HPC 中重新激活病毒如何引导分化为骨髓谱系，而且从机制上讲，单核细胞中的 HCMV 重新激活如何引导信号传导促进向生产性巨噬细胞的分化。通过我们的合作计划，我们已经确定了病毒基因（例如 UL135、US28、UL7/8）和重新激活所需的 miRNA（例如 miR-US22）。此外，通过使用缺失突变体对于无法重新激活的病毒，我们发现存在对 HCMV 重新激活的阻断，即与巨噬细胞的分化有关。对于潜伏病毒重新激活很重要的信号事件在组织巨噬细胞中的作用仍知之甚少。我们建议 UL135、US28 暂时发挥独特作用和 UL7/8 以及这些基因产物与 HCMV miRNA 的独特交叉篡夺促进这种重要细胞类型重新激活所需的信号传导的潜伏期。我们假设单核细胞向巨噬细胞分化的不同信号传导事件缓解了重新激活的阻碍这些重新激活事件是由共同努力对细胞信号传导的修改所具体驱动的这些病毒因素。为了检验我们的假设，我们提出以下目标。具体目标 1. 定义信令单核细胞和巨噬细胞中 HCMV 潜伏期和重新激活的网络。我们假设在功能上单核细胞向巨噬细胞分化的不同宿主细胞反应对于重新激活至关重要。具体的目标 2. 确定针对无法重新激活的病毒的检查点封锁。我们假设特定的失败重新激活期间的细胞信号重编程将导致细胞在表型上无法支持病毒复制。具体目标 3. 定义受感染调节的信号节点以重新激活单核细胞/巨噬细胞。我们假设 EGFR 和 RhoA 信号通路对于 HCMV 至关重要巨噬细胞的潜伏期和重新激活。影响：这些拟议的目标将使我们能够获得更深入的见解，并在我们整合我们的集体的同时工作中，我们希望将结果转化为新颖的分子特征，旨在改善结果感染仍然是移植受者的一个重大问题。