High-dimensional single-cell mapping to define immune signatures of cytomegalovirus-associated rejection in cardiac transplantation

高维单细胞图谱定义心脏移植中巨细胞病毒相关排斥反应的免疫特征

• 批准号: 10852102
• 负责人: Pritha Sen
• 金额: $ 7.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10852102
• 关键词: Acceleration; Activated Lymphocyte; Allografting; Animal Model; Antigen Presentation; Antigens; Automobile Driving; Award; Bioinformatics; Biological Markers; Biology; Biopsy; Blood; Cardiac; Cell Communication; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clonal Expansion; Communicable Diseases; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Data; Development; Development Plans; Disease; Endothelial Cells; Epithelium; Epitopes; Flow Cytometry; Fostering; Funding; General Hospitals; Genetic Transcription; Goals; Graft Rejection; Heart; Heart Transplantation; Hospitals; Human; Human Subject Research; Immune; Immune System Diseases; Immunity; Immunofluorescence Microscopy; Immunology; Immunophenotyping; Immunosuppression; In Situ Hybridization; Infiltration; Inflammasome; Inflammatory; Ligands; Longevity; Major Histocompatibility Complex; Maps; Massachusetts; Measurement; Mediating; Membrane Proteins; Memory; Mentorship; Methods; Molecular; Mononuclear; Morbidity - disease rate; Non-Invasive Detection; Oncology; Opportunistic Infections; Organ; Outcome; Phagocytes; Pharmaceutical Preparations; Phenotype; Physicians; Population; Precipitation; Production; Proteins; Proteomics; Research Personnel; Resolution; Risk; Risk Factors; Role; Scientist; System; T cell receptor repertoire sequencing; T-Cell Receptor; T-Lymphocyte Subsets; Testing; Tissues; Training; Transplant Recipients; Transplantation; Transplanted Heart Complication; Viral; Viral Cytopathogenic Effect; Viral reservoir; Viremia; Virus Diseases; Woman; Work; allograft rejection; career development; chemokine; cohort; cytotoxic; design; diagnostic tool; heart allograft; high dimensionality; high risk; immunological synapse; in vivo; isoimmunity; medical schools; multiple omics; novel; pathogen; precision medicine; programs; receptor; response; shift work; single-cell RNA sequencing; trafficking; translational study; treatment strategy

PROJECT SUMMARY Human cytomegalovirus (CMV) is the most common viral infection to complicate cardiac transplantation and is an important risk factor for cellular rejection. While CMV causes damage to native organs through direct viral cytopathic effect, CMV-mediated cardiac allograft rejection is attributed to “immune dysregulation,” the mechanisms for which are not well understood. This information is critical to the field of transplantation, as treatment of cellular rejection, even in cases with concurrent CMV viremia, includes immunosuppression, an approach that confers risk of abrogation of viremic control and precipitation of CMV-related morbidity, including worsening rejection and other opportunistic infections. While cellular rejection is mediated by cytotoxic T lymphocytes (CTL), recent paradigm-shifting work has demonstrated that activated mononuclear-phagocytic (MP) cells also have a critical role in driving allograft rejection through trained immunity. These findings are intriguing in the context of CMV-mediated graft rejection as MP cells are an important CMV viral reservoir. The central hypothesis being tested in this proposal is that CMV-mediated dysregulation of the MP system triggers a unique rejection phenotype that drives the infiltration of distinctly proliferative and alloreactive CTL into cardiac allograft tissue. The objective of this proposal is to leverage multi-omics strategies, including scRNA-seq and CITE-seq, to decode the allograft tissue microenvironment in rejection during CMV viremia, with a focus on understanding how MP cells orchestrate alloreactive CTL responses (Aim 1) and determine if tissue MP and CTL cell states are reflected in the blood (Aim 2). To accomplish this, we will study endomyocardial tissue and paired blood from a cohort of 220 heart transplant recipients at MassGeneralBrigham (MGB). These studies will distinguish CMV-mediated and CMV-independent mechanisms of cellular rejection, allowing for the development of diagnostic tools and rejection treatment strategies tailored to viral or non-viral causes, promoting precision medicine in cardiac transplantation. Dr. Sen will perform the work in this K08 proposal in the Transplant and Oncology Infectious Diseases Group at Brigham and Women’s Hospital (BWH), with continued affiliation with the Center for Immunology and Inflammatory diseases at Massachusetts General Hospital (MGH), Cell Circuits Group at the Broad Institute (MIT) and Harvard Medical School (HMS). Dr. Sen has devised a career development plan consisting of coursework, hands-on training, and expert mentorship in single-cell ‘omics,’ bioinformatics, the biology of alloimmunity and tolerance, cardiac tissue microenvironments, in vivo host- pathogen interactions, and human subjects research. The K08 award will provide Dr. Sen with the training necessary to become an independent, R01-funded investigator with expertise in host-pathogen interactions and immune dysregulation in transplantation.

项目摘要 人类巨细胞病毒（CMV）是并发症心脏移植的最常见病毒感染，是IS是IS是IS是IS是IS是IS IS IS IS IS IS IS。 细胞排斥的重要危险因素，而CMV会损害天然直接病毒 CMV介导的CardiACC Alllograft排斥反应归因于“免疫失调” 该信息对移植领域至关重要，因为 治疗细胞排斥的治疗，在同时发生CMV病毒血症的情况下，包括免疫作用， 赋予废除病毒控制和CMV相关发病降水的风险的方法，包括 拒绝和其他机会感染的恶化。 淋巴细胞（CTL），最近的范式转移工作证明了蒙古尔 - 斑道​​细胞 （MP）细胞在通过TRED的免疫力中驱动同种异体移植排斥方面也具有关键作用 在CMV介导的移植物拒绝的背景下，作为MP细胞是动画的CMV病毒储量 该提案中测试的中心假设是CMV介导的MP系统失调触发A 独特的排斥表型将明显增殖的CTL INTL渗入CardiACC 同种异体组织的目的。 引用seq，解释在CMV病毒血症期间排斥反应中的同种异体组织微环境，重点 了解MP细胞如何协调同种反应性的CTL响应（AIM 1），并确定组织MP和 CTL细胞态在血液中得到了反射（AIM 2）。 来自Masseralbrigham（MGB）的220名心脏移植受者的血液将其配对 区分CMV介导的和CMV的无关细胞排斥机制，从而允许发展 根据病毒或非病毒原因量身定制的诊断工具和拒绝治疗策略 心脏移植中的药物。 Brigham和妇女医院（BWH）的肿瘤学传染病组，并继续与之归属。 马萨诸塞州综合医院（MGH）的非动力和炎症疾病中心，细胞电路 Broad Institute（MIT）和哈佛医学院（HMS）的小组。 开发计划包括课程工作，动手培训和单细胞“ Omics”的专家指导， 生物信息学，同种免疫性和耐受性的生物学，心脏组织微型传奇，体内宿主 - 病原体相互作用和人类受试者研究将为SEN博士提供培训 成为一名独立的R01资助的研究者，具有在宿主病原体相互作用和 移植中的免疫失调。