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:
    9980283
  • 负责人:
  • 金额:
    $ 25.61万
  • 依托单位:
  • 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

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概要 人巨细胞病毒(HCMV)是一种疱疹病毒,感染44-100%的人群,并且仍然是一种高致病性病毒。 实体器官移植(SOT)和异基因造血干细胞移植中发病率和死亡率重要原因 细胞移植(SCT)受者。干细胞移植患者的感染通常与骨髓抑制和移植相关 失败是由于病毒从潜伏期重新激活,但相关的机制仍然在很大程度上是未知的。HCMV 编码多种潜伏期相关基因产物,包括趋化因子受体US 28,其结合CC- 趋化因子以及CX 3C-趋化因子Fractalkine。US 28信号在配体非依赖性和配体依赖性中均存在。 依赖的方式,但下游信号通路和后果是独特的每一个。 重要的是,在此我们证明了US 28是体外CD 34 + T细胞中的潜伏期和/或再活化所必需的。 在造血祖细胞(HPC)以及人源化小鼠模型中,此外,我们表明, US 28足以促进CD 34 + HPC分化为髓系细胞。因此,根据我们的 令人兴奋的新发现,我们假设US 28在潜伏期的配体非依赖性信号有助于维持 潜伏期和配体特异性信号传导促进CD 34 + HPC分化为再活化/复制 在一些实施方案中,病毒可以通过具有能力的骨髓谱系细胞来确保病毒在包括炎症在内的适当条件下复制。 US 28信号传导还可以通过作为生物传感器促进迁移而对潜伏期的其他方面做出贡献 炎症趋化因子,并可能通过增加早期基因表达, 重新激活定义US 28在延迟和重新激活中的作用,确定US 28信令如何交叉 EGFR信号传导,并了解US 28信号传导如何影响其他HCMV蛋白(项目1和 4)在潜伏期和操纵EGFR信号传导(项目5)期间表达的miRNA(项目2)是 这一提案的目标。我们提出了以下具体目标:1)确定US 28信号在CD 34+细胞中的作用, 使用多组学方法,HPCs与EGFR信号通路交叉; 2)为了确定哪些分子 US 28介导HCMV潜伏期和再活化的特性,使用体外CD 34 + HPC和体内 人源化BLT小鼠模型; 3)确定什么US 28信号通路促进CD 34 + HPC 还使用体外⑶ 34 + HPC和体内huBLT模型两者来观察造血。本研究结果将 产生新的病毒潜伏和再激活范例,促进新疗法的开发, 预防病毒再活化和治疗HCMV介导的骨髓抑制。

项目成果

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DANIEL N STREBLOW其他文献

DANIEL N STREBLOW的其他文献

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{{ truncateString('DANIEL N STREBLOW', 18)}}的其他基金

International Herpesvirus Workshop
国际疱疹病毒研讨会
  • 批准号:
    10752979
  • 财政年份:
    2023
  • 资助金额:
    $ 25.61万
  • 项目类别:
Project 2 - Novel Therapeutics for Emerging Alphavirus
项目 2 - 新兴甲病毒的新疗法
  • 批准号:
    10580024
  • 财政年份:
    2019
  • 资助金额:
    $ 25.61万
  • 项目类别:
Project 2 - Novel Therapeutics for Emerging Alphavirus
项目 2 - 新兴甲病毒的新疗法
  • 批准号:
    10380667
  • 财政年份:
    2019
  • 资助金额:
    $ 25.61万
  • 项目类别:
Project 2 - Novel Therapeutics for Emerging Alphavirus
项目 2 - 新兴甲病毒的新疗法
  • 批准号:
    10115598
  • 财政年份:
    2019
  • 资助金额:
    $ 25.61万
  • 项目类别:
HCMV US28 regulation of host cell signaling in viral latency and reactivation
HCMV US28 在病毒潜伏期和再激活过程中对宿主细胞信号传导的调节
  • 批准号:
    10629177
  • 财政年份:
    2017
  • 资助金额:
    $ 25.61万
  • 项目类别:
The Administrative Core
行政核心
  • 批准号:
    10629164
  • 财政年份:
    2017
  • 资助金额:
    $ 25.61万
  • 项目类别:
HCMV US28 regulation of host cell signaling in viral latency and reactivation
HCMV US28 在病毒潜伏期和再激活过程中对宿主细胞信号传导的调节
  • 批准号:
    10327950
  • 财政年份:
    2017
  • 资助金额:
    $ 25.61万
  • 项目类别:
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
  • 批准号:
    10216635
  • 财政年份:
    2017
  • 资助金额:
    $ 25.61万
  • 项目类别:
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
  • 财政年份:
    2017
  • 资助金额:
    $ 25.61万
  • 项目类别:
Characterizing the Role of CMV Latency in Solid Organ Transplant Rejection
表征 CMV 潜伏期在实体器官移植排斥中的作用
  • 批准号:
    9220714
  • 财政年份:
    2016
  • 资助金额:
    $ 25.61万
  • 项目类别:

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