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
基本信息
- 批准号:10629163
- 负责人:
- 金额:$ 257.08万
- 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 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressApoptosisBioinformaticsBiological AssayBiometryBone MarrowCD34 geneCell Differentiation processCellsClinicalCollaborationsComplexCytomegalovirusCytomegalovirus InfectionsEnvironmentEpidermal Growth Factor ReceptorEventExhibitsFundingGoalsGrowth FactorGrowth Factor ReceptorsGuanosine Triphosphate PhosphohydrolasesHematopoiesisHematopoietic Stem Cell TransplantationHematopoietic stem cellsHumanKnowledgeLife Cycle StagesLigand BindingLigandsLinkMEKsMacrophageMaintenanceMediatorMicroRNAsMolecularMorbidity - disease rateMyeloid CellsMyelopoiesisMyelosuppressionOrgan TransplantationPathway interactionsPatientsProcessProductionProductivityProteinsProto-Oncogene Proteins c-aktReceptor SignalingRegulationResearch DesignResearch Project GrantsRoleSTAT1 geneServicesShapesSignal InductionSignal PathwaySignal TransductionSolidStem cell transplantTestingTimeTissuesTransplant RecipientsViralViral ProteinsVirusVirus DiseasesVirus LatencyVirus ReplicationWorkchemokinecytokinegene interactionhumanized mouseinsightmonocytemortalitymutantnovel viruspermissivenessprogramsreactivation from latencyresponserho GTP-Binding Proteinsstem cell homeostasisstem cell proliferationstem cellssynergismtranscriptomevirus host interaction
项目摘要
SUMMARY - OVERALL
Human Cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in hematopoietic stem cell
transplant (HSCT) patients who often exhibit myelosuppression associated with virus infection. CD34+
Hematopoietic Progenitor Cells (HPCs) are a critical reservoir of latent HCMV that upon cytokine and growth
factor signals differentiate into monocytes that further differentiate into macrophages activating production of
infectious virus in tissues. Epidermal Growth Factor Receptor (EGFR) signaling pathways in CD34+ HPCs are
critical not only for determining HCMV latency and reactivation but also for regulating progenitor cell homeostasis
and hematopoiesis. Over the past 3.5 years we have identified critical EGFR signaling pathways regulated by
UL138, UL136, UL135, US28, UL7, UL8, and multiple HCMV miRNAs that are important to maintain latency or
induce viral reactivation. Most of these pathways are integrally linked with CD34+ HPC proliferation for
maintenance of the progenitor cell in the bone marrow niche as well as myelopoiesis. We have shown that
multiple HCMV miRNAs synergistically or antagonistically work together with HCMV proteins to regulate these
signaling pathways necessary for latency or viral reactivation. In addition, we have observed that UL138 is
associated with proteins involved in STAT1 signaling and that HCMV miRNAs target some of these factors. We
hypothesize that UL138-WDR48-USP1 and -USP12 interactions along with US28 and the HCMV miRNAs
regulate a STAT1 and AKT response to suppress virus replication for latency. We have also shown that US28
signaling induced by chemokines regulate latency or reactivation and is ligand specific. Additionally, we have
observed that US28 activation of RhoA is highly regulated by HCMV miRNAs as well as UL8 signaling through
the non-canonical Wnt pathway. We hypothesize that MEK/ERK signaling is essential to maintain latency while
activation of the RhoA pathway is necessary for reactivation.
While the current HCMV PPG has focused on identification of UL138, UL136, UL135, US28, UL7, and viral
miRNA EGFR signaling targets, the proposed renewal will focus on how the different HCMV genes interact with
one another to regulate these pathways and how they control the virus life cycle. 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 reactivation; Project 2:
miRNA regulation of host cell signaling in viral latency and reactivation; Project 3: US28 regulation of host cell
signaling in viral latency and reactivation; Project 4: UL7-8 regulation of host cell signaling in viral latency and
reactivation; Project 5: HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation), two
scientific cores (Humanized Mouse Core; Biostatistics and Bioinformatics Core) to service these projects, and
an Administrative Core to oversee and coordinate the entire program.
摘要-总体
人巨细胞病毒(HCMV)是造血干细胞移植中的重要致病和致死原因
HSCT患者通常表现出与病毒感染相关的骨髓抑制。CD34+
造血祖细胞(HPCs)是潜伏HCMV的重要储存库,
因子信号分化成单核细胞,单核细胞进一步分化成巨噬细胞,激活巨噬细胞的产生,
组织中的传染性病毒。CD 34 + HPC中的表皮生长因子受体(EGFR)信号通路是
不仅对确定HCMV潜伏期和再活化,而且对调节祖细胞稳态至关重要
和造血作用。在过去的3.5年中,我们已经确定了由以下因素调控的关键EGFR信号通路:
UL 138、UL 136、UL 135、US 28、UL 7、UL 8和多种HCMV miRNA,其对于维持潜伏期或
诱导病毒再活化。这些途径中的大多数与CD 34 + HPC增殖紧密相关,
维持骨髓龛中的祖细胞以及骨髓生成。我们已经证明
多个HCMV miRNA协同或拮抗地与HCMV蛋白一起作用以调节这些
潜伏期或病毒再激活所必需的信号通路。此外,我们还观察到UL 138是
与参与STAT 1信号传导的蛋白质相关,并且HCMV miRNAs靶向这些因子中的一些。我们
假设UL 138-WDR 48-USP 1和-USP 12与US 28和HCMV miRNA相互作用沿着
调节STAT 1和AKT应答以抑制病毒复制的潜伏期。我们还发现,US 28
由趋化因子诱导的信号传导调节潜伏期或再活化,并且是配体特异性的。此外,我们还有
观察到RhoA的US 28活化受到HCMV miRNA以及UL 8信号传导的高度调节,
非经典的Wnt途径。我们假设MEK/ERK信号传导对于维持潜伏期至关重要,
RhoA途径的激活对于再激活是必需的。
虽然目前的HCMV PPG专注于鉴定UL 138、UL 136、UL 135、US 28、UL 7和病毒,
miRNA EGFR信号靶点,拟议的更新将集中在不同的HCMV基因如何与EGFR相互作用。
相互调节这些途径以及它们如何控制病毒的生命周期。信令的复杂性
全面解决病毒潜伏和造血问题的活动和方法只能是
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在病毒潜伏期和再活化中对宿主细胞信号传导的调节;项目2:
病毒潜伏期和再激活中宿主细胞信号的miRNA调控;项目3:US 28对宿主细胞的调控
病毒潜伏期和再活化中的信号传导;项目4:病毒潜伏期和再活化中的宿主细胞信号传导的UL 7 -8调节
项目5:病毒再活化中单核细胞/巨噬细胞宿主细胞信号传导的HCMV调节),两个
科学核心(人源化小鼠核心;生物统计学和生物信息学核心)为这些项目提供服务,
一个行政核心来监督和协调整个计划。
项目成果
期刊论文数量(19)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Proximity-dependent mapping of the HCMV US28 interactome identifies RhoGEF signaling as a requirement for efficient viral reactivation.
- DOI:10.1371/journal.ppat.1011682
- 发表时间:2023-10
- 期刊:
- 影响因子:6.7
- 作者:
- 通讯作者:
Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation.
- DOI:10.1128/mbio.00682-18
- 发表时间:2018-04-24
- 期刊:
- 影响因子:6.4
- 作者:Crawford LB;Kim JH;Collins-McMillen D;Lee BJ;Landais I;Held C;Nelson JA;Yurochko AD;Caposio P
- 通讯作者:Caposio P
Human cytomegalovirus blocks canonical TGFβ signaling during lytic infection to limit induction of type I interferons.
- DOI:10.1371/journal.ppat.1009380
- 发表时间:2021-08
- 期刊:
- 影响因子:6.7
- 作者:Pham AH;Mitchell J;Botto S;Pryke KM;DeFilippis VR;Hancock MH
- 通讯作者:Hancock MH
Advances in Model Systems for Human Cytomegalovirus Latency and Reactivation.
- DOI:10.1128/mbio.01724-21
- 发表时间:2022-02-22
- 期刊:
- 影响因子:6.4
- 作者:Crawford LB;Diggins NL;Caposio P;Hancock MH
- 通讯作者:Hancock MH
Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions.
- DOI:10.1016/j.antiviral.2018.04.019
- 发表时间:2018-07
- 期刊:
- 影响因子:7.6
- 作者:
- 通讯作者:
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{{ truncateString('DANIEL N STREBLOW', 18)}}的其他基金
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:
$ 257.08万 - 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:
$ 257.08万 - 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:
$ 257.08万 - 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:
9980283 - 财政年份:2017
- 资助金额:
$ 257.08万 - 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:
$ 257.08万 - 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:
$ 257.08万 - 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:
$ 257.08万 - 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:
$ 257.08万 - 项目类别:
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