Integrating Mechanistic Insights from Diverse Models to Prevent CMV Reactivation following Transplantation

整合不同模型的机制见解以防止移植后 CMV 重新激活

• 批准号: 8934950
• 负责人: Michael M Abecassis
• 金额: $ 230.59万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934950
• 关键词: Acute; Animal Model; Antigens; Antiviral Agents; Bone Marrow; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell Separation; Chromatin; Chronic; Clinical; Clinical Research; Cytomegalovirus; DNA-Directed DNA Polymerase; Development; Effectiveness; Environment; Enzymes; Epigenetic Process; Fostering; Gene Expression; Goals; Graft Rejection; Health; Hematopoietic stem cells; Histones; Histopathology; Human; Immediate-Early Genes; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Kidney Transplantation; Lead; Life; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Molecular Virology; Murid herpesvirus 1; Mus; Myelogenous; Myeloid Progenitor Cells; Operative Surgical Procedures; Organ Transplantation; Outcome; Pharmaceutical Preparations; Protocols documentation; Research; Services; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Toxic effect; Transplant Recipients; Transplantation; Transplantation Tolerance; Viral; Viral Genes; Viral Genome; Virus; base; clinically relevant; design; gene repression; genome-wide; histone modification; improved; in vitro Model; in vivo; insight; lytic replication; novel strategies; prevent; programs; prophylactic; reactivation from latency; resistant strain; transcription factor; viral DNA

DESCRIPTION (provided by applicant): Overall Reactivation of latent Cytomegalovirus (CMV) remains an important clinical problem following transplantation, despite the prophylactic use of efficacious antiviral agents. Because these target the viral DNA polymerase, they are only active after the virus has reactivated from latency. Their effectiveness is also limited by toxicities and by the emergence of resistant strains. Donor- specific allo-immune tolerance, whereby a transplant recipient is hypo-responsive to donor antigens but continues to have intact immune-responsiveness to other foreign antigens has been the `Holy Grail' of transplantation since the early 1950's. Recently, several experimental protocols have achieved this goal, and the `era of tolerance' seems near. Prior studies have demonstrated that murine CMV (MCMV) reactivation requires the combination of an allo-inflammatory response and immunosuppressive drugs (ISD), while a donor-specific tolerant model would abrogate the inflammatory response, and avoid the need for ISD. Also recently, two central themes have emerged from a combination of studies of animal models of MCMV reactivation and ex vivo/in vitro models of HCMV reactivation: expression of viral genes involved in lytic replication is repressed by epigenetic factors that induce heterochromatinization of viral genomes; and signaling pathways activated by an inflammatory immune response induce reactivation of the virus through epigenetic reprogramming of viral DNA, such that the immediate early genes are released from transcriptional repression, leading to lytic replication. These themes form the basis for studies proposed in 3 separate but inter-related projects studying: 1) Mechanisms of reactivation of latent MCMV following kidney transplantation in a clinically relevant model; 2) Mechanisms of latency and reactivation of HCMV in myeloid lineage cells; and 3) MCMV infection, latency and reactivation in transplantation tolerance. Three Cores will support services needed for the successful completion of studies within these Projects: A) Microvascular surgery and histopathology; B) Precision cell isolation and analysis; and C) Administrative services. The unifying and central hypothesis of the Program Project is that reactivation of latent CMV is induced by inflammatory mediators, which activate signaling pathways, leading to epigenetic reprogramming of viral genomes, resulting in induction of immediate early (IE) gene expression, and ultimately, to reactivation of infectious virus. We believe that blockade of these signaling pathways, either by interfering with specific signaling pathways, blocking epigenetic modifications, or by donor- specific tolerance, prevent reactivation of CMV. We anticipate that integrating mechanistic insights derived from the three projects in this highly collaborative effor will be decisive in moving the field forward and in fostering the development of novel strategies to prevent, rather than treat CMV reactivation.

描述（由申请人提供）：尽管预防性使用了有效的抗病毒药物，但潜伏巨细胞病毒（CMV）的总体再激活仍然是移植后的一个重要的临床问题。因为它们以病毒 DNA 聚合酶为目标，所以它们只有在病毒从潜伏期重新激活后才具有活性。它们的有效性也受到毒性和 由于耐药菌株的出现。自 20 世纪 50 年代初期以来，供体特异性同种免疫耐受（即移植受者对供体抗原反应低下，但对其他外来抗原继续具有完整的免疫反应性）一直是移植的“圣杯”。最近，一些实验方案已经实现了这一目标，“宽容时代”似乎即将到来。先前的研究表明，小鼠 CMV (MCMV) 重新激活需要同种异体炎症反应和免疫抑制药物 (ISD) 的结合，而供体特异性耐受模型将消除炎症反应，并避免 ISD 的需要。最近，对 MCMV 再激活动物模型和 HCMV 再激活离体/体外模型的研究组合中出现了两个中心主题：参与裂解复制的病毒基因的表达受到诱导病毒基因组异染色质化的表观遗传因素的抑制；炎症免疫反应激活的信号通路通过病毒 DNA 的表观遗传重编程诱导病毒重新激活，从而使早期基因从转录抑制中释放出来，从而导致裂解性复制。这些主题构成了 3 个独立但相互关联的项目中提出的研究的基础，这些项目研究：1）临床相关模型中肾移植后潜伏 MCMV 重新激活的机制； 2) HCMV在髓系细胞中潜伏和重新激活的机制； 3) 移植耐受中的 MCMV 感染、潜伏期和再激活。三个核心将支持成功完成这些项目中的研究所需的服务：A) 微血管手术和组织病理学； B) 精密细胞分离与分析； C) 行政服务。该计划的统一和核心假设是，潜伏巨细胞病毒的重新激活是由炎症介质诱导的，炎症介质激活信号通路，导致病毒基因组的表观遗传重编程，从而诱导立即早期（IE）基因表达，并最终导致感染性病毒的重新激活。我们相信，通过干扰特定信号传导途径、阻断表观遗传修饰或通过供体特异性耐受来阻断这些信号传导途径，可以防止 CMV 重新激活。我们预计，在这一高度协作的努力中，整合从这三个项目中获得的机制见解将对于推动该领域的发展和促进开发新策略来预防而不是治疗 CMV 重新激活具有决定性作用。