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

描述（由申请方提供）：尽管预防性使用了有效的抗病毒药物，但移植后潜伏巨细胞病毒（CMV）的总体再活化仍然是一个重要的临床问题。因为这些靶向病毒DNA聚合酶，它们只有在病毒从潜伏期重新激活后才有活性。它们的有效性也受到毒性的限制， 抵抗性菌株的出现。供体特异性同种异体免疫耐受，即移植受体对供体抗原低应答，但对其它外源抗原继续具有完整的免疫应答，自20世纪50年代初以来一直是移植的“圣杯”。最近，几项实验方案已经实现了这一目标，“容忍时代”似乎即将到来。先前的研究已经证明，鼠CMV（MCMV）再活化需要同种异体炎症反应和免疫抑制药物（ISD）的组合，而供体特异性耐受模型将消除炎症反应，并避免对ISD的需要。同样在最近，从MCMV再活化的动物模型和HCMV再活化的离体/体外模型的组合研究中出现了两个中心主题：参与裂解复制的病毒基因的表达被诱导病毒基因组异染色质化的表观遗传因子抑制;并且由炎性免疫应答激活的信号传导途径通过病毒DNA的表观遗传重编程诱导病毒的再活化，使得立即早期基因从转录抑制中释放，导致裂解性复制。这些主题形成了3个独立但相互关联的项目中提出的研究基础，这些项目研究：1）临床相关模型中肾移植后潜伏MCMV再激活的机制; 2）髓系细胞中HCMV潜伏和再激活的机制; 3）移植耐受中MCMV感染、潜伏和再激活。三个核心将支持成功完成这些项目研究所需的服务：A）微血管手术和组织病理学; B）精确细胞分离和分析;以及C）行政服务。该计划项目的统一和核心假设是，潜伏性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新编程，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。我们认为，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的再激活。我们预计，在这个高度合作的effor中整合来自三个项目的机制见解将决定性地推动该领域的发展，并促进新策略的发展，以预防而不是治疗CMV再激活。

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.