Human anti-viral immune responses in tissues and circulation

人体组织和循环中的抗病毒免疫反应

• 批准号: 10201036
• 负责人: Donna L. Farber
• 金额: $ 16.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-28 至 2022-03-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201036
• 关键词: Active Sites; Affect; Age; Aging; Agonist; Antiviral Agents; Antiviral Response; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood specimen; Cell physiology; Cells; Clinical; Clinical Management; Cytomegalovirus; Cytomegalovirus Infections; Cytometry; Data; Data Analyses; Data Set; Databases; Dendritic Cells; Disease; Disease Progression; Endocrine; Goals; HIV Infections; Health; Herpesviridae; High-Throughput RNA Sequencing; Homeostasis; Human; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunosuppression; Immunotherapy; In Situ; Individual; Infection; Infectious Agent; Intestines; Investigation; Knowledge; Laboratories; Life; Longevity; Lung; Lymphoid; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Measures; Modeling; Molecular Profiling; Mucous Membrane; Natural Immunity; New York City; Office of Administrative Management; Organ; Organ Donor; Organ Procurements; Organ Transplantation; Output; Peripheral; Population; Proteome; Proteomics; Protocols documentation; Research; Resources; Sampling; Services; Site; Stimulus; System; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; Time; Tissue Differentiation; Tissues; Transplant Recipients; Transplantation; Vaccination; Vaccines; Viral; Viremia; Virus; Virus Diseases; adaptive immune response; adaptive immunity; base; chemotherapy; clinically relevant; cohort; data management; effector T cell; human tissue; immunosenescence; improved; in vivo; lymph nodes; macrophage; mortality; mouse model; novel; pathogen; pathogenic virus; peripheral blood; programs; response; seropositive; tissue resource; transcriptome sequencing; transcriptomics

Program Summary Studies of human immune responses to viruses and other pathogens have focused, by necessity, on sampling of peripheral blood; however, innate and adaptive immune responses are initiated, function and maintained in diverse tissue sites. Innate cells, including tissue macrophages and dendritic cells (DC) that encounter pathogens at key entry points (e.g., lungs, intestines) do not appear in circulation. Similarly T cells infiltrate infection sites and can persist as non-circulating tissue-resident memory T cells, which provide protective responses in situ. At present, our understanding of tissue-localized innate and adaptive immune responses is based on mouse models, and we lack fundamental knowledge on how innate and adaptive cells are organized and function in human tissues. The overall goal of this research program in human immunity is to obtain in- depth profiles of how human innate and adaptive immune cells in tissues respond to viral infection, with a focus on the globally pervasive herpesvirus, Cytomegalovirus (CMV). CMV establishes lifelong persistence in multiple sites, has broad effects on aging and immunity, and can be reactivated during immunosuppression in transplantation and cancer, causing serious disease and mortality. The proposed research program, consisting of three projects, and five cores, will obtain in-depth profiles of human immune cells involved in controlling CMV in human tissue sites using our unique tissue resource where lymphoid, mucosal and peripheral tissue are obtained from individual organ donors, compared to blood responses from living cohorts with active infection. Project 1 (PL: Farber) will study T cell responses to CMV in tissues and circulation from organ donors and transplant patients; Project 2 (PI: B. Reizis) will study how DC subsets in different sites functionally respond to CMV and CMV-infected cells from both tissues and cohorts of transplant patients; and Project 3 (PI: M. Merad) will profile macrophages in tissues and their responses to innate stimuli through TLR agonists and CMV, and effect of CMV infection on macrophage function. The administrative core will coordinate organization and financial aspects of the program, the Clinical Core will provide all samples including tissues from organ donors and blood samples from transplant cohorts to the three projects. The Transcriptomics (RNAseq) and single cell core (Core A) will provide high throughput RNA sequencing on the population and single cell level, and multidimensional proteome profiling using cytometry by time-of-flight (CyTOF). The Viral assays core (Core B) will measure CMV persistence in different tissue sites to dissect how virus persistence impacts tissues immune responses. The data management and analysis core (DMAC) will store, curate and analyze all data outputs from the projects and cores, apply bioinformatics for analysis of transcriptomic and proteomic data, generate models to integrate the datasets, and submit raw data to public databases such as ImmPort and NCBI. The results from this program will identify signatures for tissue-specific control of human immune responses for promoting in situ protective immunity in vaccines and immunotherapies.

程序摘要 人类免疫反应对病毒和其他病原体的反应已无需将其集中在取样上 外周血；但是，先天和适应性免疫反应启动，功能并保持 多种组织部位。先天细胞，包括遇到的组织巨噬细胞和树突状细胞（DC） 关键入口点处的病原体（例如，肺，肠）不会出现在循环中。类似地T细胞浸润 感染部位，可以作为非循环组织居住的记忆T细胞持续存在，可提供保护性 原位响应。目前，我们对组织关闭的先天和适应性免疫反应的理解是 基于小鼠模型，我们缺乏有关如何组织天生和自适应细胞的基本知识 并在人体组织中的功能。该研究计划的人类免疫力的总体目标是获得 人类先天和适应性免疫细胞在组织中如何反应病毒感染的深度谱图，重点 在全球普遍存在的疱疹病毒上，巨细胞病毒（CMV）。 CMV在 多个部位对衰老和免疫力具有广泛的影响，可以在免疫抑制期间重新激活 移植和癌症，导致严重的疾病和死亡率。拟议的研究计划，包括 在三个项目和五个核心中，将获得与控制有关的人类免疫细胞的深入分布 使用我们独特的组织资源的人类组织部位的CMV，其中淋巴，粘膜和周围组织 与活跃的活人同龄人的血液反应相比，从单个器官捐献者那里获得 感染。项目1（PL：FARBER）将研究组织对CMV的T细胞反应和器官捐献者的循环 和移植患者；项目2（PI：B。Reizis）将研究不同站点的DC子集在功能上如何 对来自移植患者的组织和人群的CMV和CMV感染细胞反应；和项目3（PI： M. Merad）将通过TLR激动剂和对先天刺激的组织中的巨噬细胞以及它们对先天刺激的反应 CMV，以及CMV感染对巨噬细胞功能的影响。行政核心将协调组织 和该计划的财务方面，临床核心将提供所有样本，包括来自器官的组织 从移植人群到这三个项目的捐助者和血液样本。转录组学（RNASEQ）和 单细胞核（核心A）将在种群和单细胞水平上提供高吞吐量RNA测序， 以及通过飞行时间（Cytof）的细胞仪进行多维蛋白质组分析。病毒测定核心 （核B）将测量不同组织部位的CMV持久性，以剖析病毒持久性的影响 组织免疫反应。数据管理和分析核心（DMAC）将存储，策划和分析所有 来自项目和核心的数据输出，应用生物信息学用于分析转录组和蛋白质组学 数据，生成模型以集成数据集，并将原始数据提交给Immport等公共数据库 和NCBI。该程序的结果将确定针对人类免疫组织特异性控制的签名 促进疫苗和免疫疗法中原位保护性免疫的反应。