Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency, reactivation, and hematopoiesis during transplantation

总体项目总结/摘要 本研究的目的是阐明HCMV对宿主细胞信号转导的分子调控机制。 建立和维持病毒潜伏期和再激活，并确定病毒如何失调， CD 34+造血祖细胞（HPC）信号转导可能会损害造血。HCMV仍然是一种 实体器官移植（SOT）和造血干细胞移植后发病率和死亡率的重要原因 细胞移植（HSCT）和骨髓抑制是HCMV感染的常见临床表现， 这些病人。HPC代表移植受体中潜伏HCMV的关键储库，从而提供了 病毒传播到内脏器官的来源。 我们的研究组使用体外CD 34 + HPC模型和植入人胎骨的小鼠的初步数据 骨髓、肝脏和胸腺（huBLT小鼠）已经表明，HCMV对表皮生长因子的调节 CD 34 + HPC中的受体（EGFR）和下游信号传导对于病毒潜伏和再活化至关重要， 以及造血功能。我们的研究小组已经表明，在潜伏感染的CD 34+细胞中表达多种HCMV基因， 包括UL 133 -138基因座、US 28、UL 7和HCMV miRNA的HPC靶向多个信号通路 通过EGFR激活以控制病毒潜伏/再激活和造血。我们假设巨细胞病毒 调节EGFR及其下游通路的活性，以平衡病毒潜伏和再活化状态。我们 还假设HCMV微调信号传导和细胞因子分泌以影响造血。我们还 我认为，这种调节满足了促进传播但限制广泛造血的拮抗需求 分化以控制再活化。 本计划项目将使用体外CD 34 + HPC模型组合测试这些假设中的每一个 使用huBLT小鼠模型和来自SOT和HSCT患者的样品。信号事件的复杂性 全面解决病毒潜伏期和造血问题的方法只能是 这是在项目付费机制下通过合作努力实现的。因此，我们提出了五个高度集成的 研究项目（项目1：UL 133/8在病毒潜伏和造血中调节宿主细胞信号传导; 项目2：HCMV miRNA在病毒潜伏期和造血中对宿主细胞信号传导的调节;项目3：HCMV US 28在病毒潜伏期和造血中调节宿主细胞信号传导;项目4： 病毒潜伏期和造血中的宿主细胞信号传导;项目5：宿主细胞信号传导和 骨髓抑制中的细胞因子），两个科学核心（人源化小鼠核心;基因组学，生物统计学和 生物信息学核心）为这些项目提供服务，行政核心负责监督和协调整个 程序.

OVERALL PROJECT SUMMARY/ABSTRACT The goal of our program is to elucidate the molecular mechanisms of HCMV regulation of host signaling in the establishment and maintenance of viral latency and reactivation, and determine how viral dysregulation of CD34+ Hematopoietic Progenitor Cells (HPCs) signaling may compromise hematopoiesis. HCMV remains a significant cause of morbidity and mortality after Solid Organ Transplantation (SOT) and Hematopoietic Stem Cell Transplantation (HSCT), and myelosuppression is a common clinical manifestation of HCMV infection in these patients. HPCs represent a critical reservoir of latent HCMV in the transplant recipient, thereby providing a source of virus for dissemination to visceral organs. Preliminary data from our group using an in vitro CD34+ HPC model and mice engrafted with human fetal bone marrow, liver and thymus (huBLT mice) have shown that HCMV regulation of Epidermal Growth Factor Receptor (EGFR) and downstream signaling in CD34+ HPCs is essential for viral latency and reactivation as well as hematopoiesis. Our group has shown that multiple HCMV genes expressed in latently infected CD34+ HPCs including the UL133-138 locus, US28, UL7 and HCMV miRNAs target multiple signaling pathways activated by EGFR to control viral latency/reactivation and hematopoiesis. We hypothesize that HCMV fine tunes the activity of EGFR and its downstream pathways to balance states of viral latency and reactivation. We also hypothesize that HCMV fine tunes signaling and cytokine secretion to impact hematopoiesis. Further, we propose that this regulation meets antagonistic needs to promote dissemination but limit broad hematopoietic differentiation to control reactivation. This program project will test each of these hypotheses using the in vitro CD34+ HPC model in combination with the huBLT mouse model and samples from SOT and HSCT patients. 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 hematopoiesis; Project 2: HCMV miRNA regulation of host cell signaling in viral latency and hematopoiesis; Project 3: HCMV US28 regulation of host cell signaling in viral latency and hematopoiesis; Project 4: HCMV UL7 regulation of host cell signaling in viral latency and hematopoiesis; Project 5: HCMV regulation of host cell signaling and cytokines in myelosuppression), two scientific cores (Humanized Mouse Core; Genomics, Biostatistics and Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire program.