Role of innate immunity and injury in transplant-induced reactivation of MCMV

先天免疫和损伤在移植诱导的 MCMV 重新激活中的作用

• 批准号: 8227285
• 负责人: Michael M Abecassis
• 金额: $ 19.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8227285
• 关键词: B-Lymphocytes; Blood flow; Bone Marrow Transplantation; Cells; Chromatin; Clinical; Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; Development; Disease; Economic Inflation; Endothelial Cells; Enhancers; Environment; Foundations; Frequencies; Gene Expression; Goals; Graft Rejection; Herpesviridae; Immediate-Early Genes; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunosuppression; Individual; Infection; Infection Control; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Investigation; Kidney; Kidney Transplantation; Kinetics; Latent Virus; Lead; Macrophage-1 Antigen; Mediating; Memory; Modeling; Molecular; Morbidity - disease rate; Murid herpesvirus 1; Mus; Natural Immunity; Natural Killer Cells; Neutrophil Infiltration; Newborn Infant; Nitrogen; Organ; Organ Transplantation; Oxygen; Patients; Pattern; Pattern recognition receptor; Peptide Hydrolases; Population; Prevention; Proteins; Protocols documentation; Reactive Oxygen Species; Recruitment Activity; Reperfusion Injury; Repression; Risk; Role; Serum Markers; Signal Pathway; Site; Solid; Species Specificity; Sterility; T cell response; T memory cell; T-Lymphocyte; Testing; Tissues; Transcription Factor AP-1; Transplant Recipients; Transplantation; Treatment Efficacy; Up-Regulation; Vascular blood supply; Viral; Viral Genes; Viral Genome; Virus; activated Protein C; activating transcription factor; base; cell injury; chemokine; cytokine; in vivo; latent infection; macrophage; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; pathogen; prevent; reactivation from latency; receptor; receptor for advanced glycation endproducts; response; transcription factor; translational study; viral DNA

DESCRIPTION (provided by applicant): Reactivation of latent CMV is frequently observed in recipients of solid organ and bone marrow transplants and is a significant cause of morbidity and mortality in immunocompromised hosts. Due to the species specificity of HCMV, investigation of the factors that induce reactivation in transplant recipients has been hampered by the lack of appropriate models that recapitulate the complexity of the in vivo environment. Therefore, we have used MCMV as a model to study latency and reactivation. Whereas we have previously focused on immunocompetent mouse models, we have more recently developed a new transplant model for reactivation of infectious virus, in which kidneys from latently infected mice are transplanted into immunocompromised NOD.Cg-PrkdcscidIL2rgtm1Wjl/Szj (NSG) recipients, which lack functional B, T, and NK cells. Reactivation in this model occurs slowly and sporadically over a period of 2-6 weeks, and results in a disseminated infection that spreads from the transplanted kidney to other recipient organs. The kinetics of reactivation in this model is similar to that observed in transplant recipients treated with standard immunosuppression protocols. Thus, our new model is highly relevant to the clinical setting of CMV disease and allows us to explore novel mechanisms responsible for primary CMV infection in transplant recipients. We hypothesize that reactivation in this model is due to activation of viral gene expression initiated by ischemia/reperfusion (I/R) injury, which leads to a sterile inflammatory response mediated by innate immune cells. I/R injury causes formation of damage associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors on innate immune cells, up-regulation of chemokines that recruit inflammatory cells, which cause further damage through release of reactive oxygen and nitrogen species and proteolytic enzymes, and cytokines that activate signaling pathways leading to activation of transcription factors that control MCMV immediate early gene expression. In the absence of an adaptive immune response, we hypothesize that this leads to reactivation of infectious virus. In this application we propose to characterize markers of injury in this model and to investigate the requirement for neutrophils and macrophages in reactivation. In addition, we will investigate the therapeutic efficacy of activated protein C in blocking reactivation. This protein is currently in use clinically for prevention of kidney injury. These translational studies could provide the basis for clinical trials to investigate novel therapies to prevent reactivation of CMV from latency in immunocompromised patients. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) is a ubiquitous herpesvirus which establishes a lifelong latent infection, and reactivation of latent virus can cause significant morbidity or mortality in immunocompromised patients. The goal of this application is to understand cellular mechanisms leading to reactivation of murine cytomegalovirus in immunocompromised transplant recipients. These studies may lead to development of new therapies to prevent reactivation of latent CMV and its sequelae.

描述（由申请方提供）：在实体器官和骨髓移植受者中经常观察到潜伏CMV的再活化，并且是免疫功能低下宿主发病和死亡的重要原因。由于HCMV的种属特异性，研究移植受体中诱导再活化的因素受到缺乏适当模型的阻碍，该模型概括了体内环境的复杂性。因此，我们使用MCMV作为模型来研究潜伏期和再激活。鉴于我们以前专注于免疫活性小鼠模型，我们最近开发了一种新的移植模型，用于感染性病毒的再活化，其中将潜伏感染小鼠的肾脏移植到免疫功能低下的NOD. Cg-PrkdcscidIL 2 rgtm 1 Wjl/Szj（NSG）受体中，这些受体缺乏功能性B、T和NK细胞。该模型中的再活化在2-6周的时间内缓慢且零星地发生，并导致从移植肾扩散到其他受体器官的播散性感染。该模型中的再活化动力学与用标准免疫抑制方案治疗的移植受体中观察到的相似。因此，我们的新模型与CMV疾病的临床背景高度相关，并使我们能够探索移植受者原发性CMV感染的新机制。我们假设，在这个模型中的再激活是由于激活的病毒基因表达启动缺血/再灌注（I/R）损伤，导致先天免疫细胞介导的无菌炎症反应。I/R损伤导致损伤相关分子模式（DAMP）的形成，其被先天免疫细胞上的模式识别受体识别，募集炎性细胞的趋化因子的上调，其通过释放活性氧和氮物质以及蛋白水解酶引起进一步损伤，以及激活信号传导途径的细胞因子，其导致控制MCMV立即早期基因表达的转录因子的激活。在缺乏适应性免疫应答的情况下，我们假设这导致感染性病毒的重新激活。在这个应用程序中，我们建议在这个模型中的损伤的标志物的特点，并调查中性粒细胞和巨噬细胞的再激活的要求。此外，我们还将研究活化蛋白C在阻断再活化方面的治疗效果。这种蛋白质目前在临床上用于预防肾损伤。这些转化研究可以为临床试验提供基础，以研究新的治疗方法，以防止免疫功能低下患者的CMV潜伏期再激活。 公共卫生相关性：巨细胞病毒（CMV）是一种普遍存在的疱疹病毒，可造成终身潜伏感染，潜伏病毒的再激活可导致免疫功能低下患者的显著发病率或死亡率。本申请的目的是了解导致免疫功能低下的移植受者中鼠巨细胞病毒再活化的细胞机制。这些研究可能会导致新的治疗方法的发展，以防止潜伏CMV及其后遗症的再激活。