HCMV regulation of host cell signaling and cytokines in myelosuppression

HCMV 在骨髓抑制中对宿主细胞信号传导和细胞因子的调节

基本信息

批准号：
9980285
负责人：
ANDREW D YUROCHKO
金额：
$ 21.29万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980285
关键词：
Allogenic Animal Model Antiviral Agents BLT mice Back Bacterial Infections Blood Transfusion Bone Marrow CD34 gene Cell Differentiation process Cells Chemicals Clinical Cytomegalovirus Data Development Disease Engraftment Failure Ganciclovir Genetic Transcription Goals Growth Factor Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human In Vitro Individual Infection Intervention Investigation Mediating MicroRNAs Modeling Molecular Molecular Profiling Morbidity - disease rate Mycoses Myelopoiesis Myelosuppression Organ Transplantation Organism Pathway interactions Patients Pharmacology Process Regulation Risk Role Sampling Signal Pathway Signal Transduction Solid Stem cell transplant System Testing Transcript Transplant Recipients Transplantation Viral Genes Viral Pathogenesis Viral Proteins Virus Virus Latency Work blood product clinical development clinical encounter clinically relevant cytokine cytopenia humanized mouse improved outcome in vivo in vivo Model inhibitor/antagonist insight knock-down mortality mouse model multiple omics novel virus predictive signature reconstitution repaired small hairpin RNA targeted treatment therapy design transcriptome virus host interaction virus identification

项目摘要

PROJECT 5 PROJECT SUMMARY Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality after Hematopoietic Stem Cell Transplantion (HSCT) and Solid Organ Transplantation (SOT). A commonly encountered clinical manifestation of HCMV infection in the HSCT or SOT recipient is myelosuppression. HCMV reactivation and use of the antiviral ganciclovir is associated with a number of cytopenias that increase the risk of secondary bacterial or fungal infections and require growth factor support or transfusion of blood products. Despite the clear clinical relevance of myelosuppression to the transplant recipient with HCMV infection, little is known about the mechanism(s) by which HCMV infection inhibits normal hematopoiesis. HCMV has been shown to inhibit hematopoiesis by the direct infection of hematopoietic progenitor cells (HPCs) and indirectly by the effect of infected HPCs on the microenvironment supporting hematopoiesis. We have recapitulated HCMV myelosuppression in vivo using a humanized mouse model. We further show in both in vitro and in vivo models that the addition of increasing numbers of infected CD34+ HPCs increases the degree of myelosuppression and that supernatant from infected CD34+ HPCs, as opposed to mock-infected HPCs, suppresses myelopoiesis. Further, Projects 1, 2, 3 and 4 have identified viral proteins and miRNAs that directly alter signaling and either promote or suppress hematopoiesis in vitro. Therefore, we hypothesize that HCMV infection reprograms signaling and cytokine secretion in infected cells resulting in a microenvironment that inhibits hematopoiesis and contributes to clinical myelosuppression and hematopoietic failure. To test our hypothesis, we propose a systems approach to define the changes in signaling and cytokine secretion using both in vitro and in vivo models. We propose the following specific aims. Specific Aim 1. How does HCMV infection of CD34+ HPCs in vitro regulate hematopoiesis? We hypothesize that HCMV suppresses CD34+ HPC differentiation by altering signaling and secretion in the infected cell. Specific Aim 2. How does HCMV regulate hematopoiesis in vivo? We hypothesize that HCMV infection alters the microenvironment for hematopoiesis in the host organism. Specific Aim 3. What are the molecular signatures associated with HCMV myelosuppression in HSCT and SOT patients? We hypothesize that HCMV-mediated changes in cytokine secretion impede hematopoietic reconstitution in HSCT and SOT patients. IMPACT: Taken together, our project provides a unique opportunity to make unprecedented advancements in our understanding of the mechanistic basis of HCMV-mediated myelosuppression. This advancement is driven by the development of the state-of-the-art huBLT mouse model and the identification of virus-host interactions impacting hematopoiesis and the key cytokine and molecular signatures that predict disease.

项目 5 项目摘要人类巨细胞病毒（HCMV）仍然是造血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）临床常见。 HSCT或SOT受体中HCMV感染的表现是HCMV再激活和骨髓抑制。使用抗病毒药物更昔洛韦与许多血细胞减少症相关，从而增加继发性风险细菌或真菌感染，需要生长因子支持或输注血液制品。骨髓抑制与 HCMV 感染的移植受者的明确临床相关性，目前知之甚少关于 HCMV 感染抑制正常造血的机制已被证明。通过直接感染造血祖细胞（HPC）和间接感染抑制造血受感染的 HPC 对支持造血的微环境的影响。我们使用人源化小鼠模型在体内重现了 HCMV 骨髓抑制。在体外和体内模型中进一步表明，添加越来越多的受感染 CD34+ HPC 增加骨髓抑制的程度以及受感染 CD34+ HPC 的上清液，而不是此外，项目 1、2、3 和 4 还鉴定了病毒蛋白。以及直接改变信号传导并促进或抑制体外造血的 miRNA。 HCMV 感染会重新编程受感染细胞中的信号传导和细胞因子分泌，从而导致抑制造血并有助于临床骨髓抑制和造血的微环境为了检验我们的假设，我们提出了一种系统方法来定义信号传导和细胞因子的变化。我们提出以下具体目标 1. 如何进行。体外 CD34+ HPC 的 HCMV 感染是否调节造血功能？我们假设 HCMV 会抑制造血作用？ CD34+ HPC 通过改变受感染细胞中的信号传导和分泌来分化。具体目标 2。 HCMV 调节体内造血？我们发现 HCMV 感染会改变微环境具体目标 3. 与 HCMV 相关的分子特征是什么。 HSCT 和 SOT 患者的骨髓抑制？我们欺负 HCMV 介导的细胞因子变化分泌物阻碍 HSCT 和 SOT 患者的造血重建。影响：总的来说，我们的项目提供了一个独特的机会来取得前所未有的进步在我们对 HCMV 介导的骨髓抑制机制基础的理解中，这一进展是。由最先进的 huBLT 小鼠模型的开发和病毒宿主的识别驱动影响造血作用以及预测疾病的关键细胞因子和分子特征的相互作用。