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

• 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
• 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

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 人巨细胞病毒（HCMV）是造血干细胞移植后发病和死亡的重要原因。 干细胞移植（HSCT）和实体器官移植（SOT），由于这些疾病的再活化或新感染， 移植接受者我们联合PPG实验室已经表明，CD 34+造血细胞的HCMV感染 祖细胞（HPCs）的HCMV潜伏期和随后的再活化的位点改变造血事件， 有利于HPC向髓系分化。为了充分了解HCMV再激活过程，我们需要 不仅了解CD 34 + HPC中病毒的再活化如何引导细胞分化的过程， 骨髓谱系，但也在机制上如何HCMV在单核细胞中的再活化指导信号传导， 促进向多产巨噬细胞分化。 通过我们的合作计划，我们已经确定了病毒基因（例如，UL 135、US 28、UL 7/8）和 重新激活所需的miRNA（例如miR-US 22）。此外，通过使用缺失突变体， 对于不能再活化的病毒，我们已经确定了HCMV再活化的障碍， 与分化成巨噬细胞有关。潜伏病毒再激活的重要信号事件 在组织巨噬细胞中仍然知之甚少。我们建议UL 135、US 28在时间上具有独特的作用 和UL 7/8，以及这些基因产物与HCMV miRNAs表达的独特交叉， 潜伏期篡夺必要的信号，以促进在这种必要的细胞类型的再活化。我们 假设单核细胞向巨噬细胞分化中不同信号传导事件解除了对再活化的阻断 并且这些再激活事件是由细胞信号传导的修改所特别驱动的， 这些病毒因素。为了验证我们的假设，我们提出了以下目标。具体目标1.定义信令 单核细胞和巨噬细胞中HCMV潜伏期和再活化的网络。我们假设在功能上 单核细胞向巨噬细胞分化中不同的宿主细胞应答对于再活化是必需的。具体 目标2.确定无法重新激活的病毒的检查点封锁。我们假设，在特定的失败， 在再活化期间细胞信号重编程将导致细胞表型上不能支持 病毒复制具体目标3。定义受感染调节的信号节点，以便在 单核细胞/巨噬细胞。我们假设EGFR和RhoA信号通路对HCMV的发生和发展至关重要。 巨噬细胞的潜伏期和再激活。 影响：这些拟议的目标将使我们能够获得更大的洞察力， 工作，我们希望将结果转化为新的分子签名，旨在改善一个 感染仍然是移植受者的一个重要问题。