Comprehensive analysis of human adaptive immune receptors to elucidate correlates of Epstein-Barr virus disease suppression

全面分析人类适应性免疫受体以阐明 Epstein-Barr 病毒疾病抑制的相关性

• 批准号: 10619219
• 负责人: Brandon James DeKosky
• 金额: $ 36.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619219
• 关键词: Comprehensive; analysis; human; adaptive; immune

Project Summary/Abstract This project will develop a new technological approach for the comprehensive analysis of adaptive immune responses, which holds the potential to catalyze new strategies to prevent and treat disease. Here we will apply immune profiling techniques recently invented by the PI to investigate the mechanisms of Epstein-Barr virus (EBV) adaptive immune control in clinical cohorts of infected patients. EBV is a highly prevalent pathogen infecting >90% of the world’s population. Primary EBV infection often causes infectious mononucleosis (IM) and long-term sequelae include numerous malignancies, lymphoproliferative disorders, and a strong association with multiple sclerosis. No EBV vaccine is approved to date, and the molecular mechanisms of immune protection from EBV-associated diseases are unclear. Unfortunately, prior technical barriers in high- throughput immune profiling methods have prevented a comprehensive understanding of adaptive immune protection against EBV diseases. A technological approach that identifies the critical features of EBV immune protection will advance new solutions for vaccine and therapeutic development. Therefore, we developed an experimental pipeline to enable rapid and cost-effective analysis of B- and T-cell responses to EBV that is scalable to dozens of human patients per experiment. We hypothesize that a comprehensive B- and T-cell analysis of carefully selected patient cohorts that either can or cannot suppress symptomatic infection will reveal function-based correlates of EBV control. To test this hypothesis, we will apply quantitative immune profiling technologies to analyze cryopreserved longitudinal samples from recently completed prospective clinical studies of IM. Patient samples in our cohort span pre- and post-infection through convalescence and encompass the full range of clinical IM severity scores (from 0, asymptomatic primary infection, to 6, essentially bedridden with IM). Immune profile data will be used to establish adaptive immune correlates of IM disease severity. In addition, we will analyze immune responses in apparently immunocompetent patients with chronic active EBV (CAEBV) disease, or patients who do not adequately suppress EBV infection, to gain insight regarding adaptive immune function and dysfunction in CAEBV. Finally, we will develop a new computational toolkit to rapidly identify immune correlates from high-throughput datasets. Successful completion of this project will constitute the first comprehensive functional B- and T-cell receptor analysis in a human clinical cohort. Our efforts will provide a repertoire-scale, mechanistic understanding of adaptive immunity to EBV and suggest new strategies for treatment and prevention of EBV-associated diseases. Our long-term goal is to develop human immune profiling techniques as a platform approach to accelerate the rational design of vaccines and therapeutics against pathogens of high public health importance, beginning with EBV.

项目概要/摘要 该项目将开发一种用于适应性免疫综合分析的新技术方法 反应，这有可能促进预防和治疗疾病的新策略。 应用 PI 最近发明的免疫分析技术来研究 Epstein-Barr 的机制 EBV 病毒 (EBV) 的适应性免疫控制在感染患者的临床队列中是一种高度流行的病原体。 感染世界上 90% 以上的人口，原发性 EBV 感染通常会导致传染性单核细胞增多症 (IM)。 和长期后遗症包括许多恶性肿瘤、淋巴增殖性疾病和强烈的 迄今为止，还没有批准 EBV 疫苗与多发性硬化症的相关性，以及其分子机制。 不幸的是，针对 EBV 相关疾病的免疫保护尚不清楚。 吞吐量免疫分析方法阻碍了对适应性免疫的全面理解 一种识别 EBV 免疫关键特征的技术方法。 保护将推动疫苗和治疗开发的新解决方案。 实验管道能够快速且经济高效地分析 B 细胞和 T 细胞对 EBV 的反应， 每个实验可扩展到数十名人类患者，我们使用了全面的 B 细胞和 T 细胞。 对精心挑选的能够或不能抑制症状感染的患者群体进行分析将 揭示 EBV 控制的基于功能的相关性 为了检验这一假设，我们将应用定量免疫。 用于分析来自最近完成的预期的冷冻保存的纵向样本的分析技术 我们队列中的患者样本涵盖了感染前和感染后、康复期和康复期。 涵盖全部临床 IM 严重程度评分（从 0（无症状原发感染）到 6（无症状原发感染） 免疫特征数据将用于建立 IM 的适应性免疫相关性。 此外，我们将分析明显免疫功能正常的患者的免疫反应。 慢性活动性 EBV (CAEBV) 疾病或不能充分抑制 EBV 感染的患者，以获得 关于 CAEBV 适应性免疫功能和功能障碍的见解最后，我们将开发一种新的方法。 计算工具包，用于从高通量数据集中快速识别免疫相关性。 该项目的完成将构成首次全面的功能性 B 细胞和 T 细胞受体分析。 我们的努力将为适应性提供全面的、机械的理解。 EBV 免疫并提出治疗和预防 EBV 相关疾病的新策略。 长期目标是开发人类免疫分析技术作为平台方法，以加速 针对具有高度公共卫生重要性的病原体的疫苗和疗法的合理设计，开始 与 EBV。