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.

项目摘要/摘要 该项目将为适应性免疫的综合分析开发一种新的技术途径。 反应，这有可能催生预防和治疗疾病的新战略。在这里，我们将 应用新近发明的免疫图谱技术研究Epstein-Barr的发病机制 病毒(EBV)感染患者临床队列的适应性免疫控制。EB病毒是一种高度流行的病原体。 感染了世界90%的人口。原发性EBV感染常引起传染性单核细胞增多症 长期的后遗症包括许多恶性肿瘤、淋巴增生性疾病和强烈的 与多发性硬化症有关。到目前为止，还没有EBV疫苗被批准，而且EBV的分子机制 针对EBV相关疾病的免疫保护尚不清楚。不幸的是，之前的技术壁垒在高- 吞吐量免疫分析方法阻碍了对适应性免疫的全面理解 预防EB病毒疾病。一种确定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。因此，我们开发了一种 实验流水线，使快速和经济有效的分析B细胞和T细胞对EBV的反应，即 每个实验可扩展到数十名人类患者。我们假设一个综合的B细胞和T细胞 对精心挑选的能够或不能抑制症状性感染的患者队列进行分析将 揭示基于功能的EBV控制的相关性。为了验证这一假设，我们将应用数量免疫。 用于分析新近完成的远景标本的冷冻保存的纵向样品的剖析技术 肠化生的临床研究。我们队列中的患者样本跨越感染前和感染后的恢复期和 涵盖所有临床IM严重程度评分(从0，无症状的初次感染，到6， 基本上是卧床不起的即时通讯)。免疫档案数据将用于建立IM的适应性免疫关联 疾病的严重性。此外，我们将分析明显具有免疫功能的患者的免疫反应。 慢性活动性EB病毒(CAEBV)病，或没有充分抑制EBV感染的患者，以获得 关于CAEBV获得性免疫功能和功能障碍的见解。最后，我们将开发一种新的 用于从高通量数据集中快速识别免疫关联的计算工具包。成功 该项目的完成将构成第一个全面的功能性B细胞和T细胞受体分析 人类临床队列。我们的努力将提供一个曲目规模的，机械的理解自适应 对EB病毒的免疫力，并为治疗和预防EBV相关疾病提出新的战略。我们的 长期目标是开发人类免疫图谱技术作为一种平台方法来加速 合理设计针对具有高度公共卫生重要性的病原体的疫苗和治疗方法 带着EB病毒。