Human immune signatures of Dengue virus and Mycobacterium Tuberculosis exposure in infection, disease and vaccination

 描述(由申请人提供)：我们应用的基本前提是提供与人类疾病相关的无偏见、非假设驱动的免疫特征(IMS)分析。我们将阐明特定的IMS是否与某些已定义的亚集的优先扩张/收缩有关，这些亚集已经在生理上和内稳态地存在于个体的T细胞池中，并且在很大程度上保持了其特有的IMS。我们还将考虑另一种可能性，即IMS的变化反映了具有分化/激活的不同T细胞亚群的生成 与感染、疾病和疫苗接种有独特联系的国家。在不同的人类病原体系统和不同的地理位置处理这些问题，将有可能确定所获得的结果在多大程度上是普遍适用的。因此，我们建议从1)自然免疫和/或感染控制，2)活动性和严重疾病，以及3)接种许可或实验疫苗的背景下，来描述与结核分枝杆菌(MTB)和登革病毒(DENV)相关的CD4和CD8记忆T细胞IMS。我们小组研究MTB和DENV已有数年之久，原因如下。1.它们都是当前的全球健康问题。2.对于这些疾病，记忆T细胞基本上与保护性免疫有关。3.在体外可检测到足够数量的抗原特异性T细胞反应，从而无需体外扩增或刺激即可进行“组学”研究。4.与自然感染/免疫和严重疾病有关的人类标本很容易获得。因此，我们开发了一种被广泛利用的临界量，其基础是：1)经验丰富的LJI研究人员的成熟团队，2)与该领域的领导者建立了临床合作，确保将实现招募大量特征合适的个人的目标(事实上，已有数百个样本可用)，3)数百个受各种不同的HLAI和II类分子限制的表位，以允许以前所未有的精度分析记忆T细胞4)现有数据确定特定的T细胞亚群是免疫中的关键角色，5)建立并验证了用于生成与MTB和DENV相关的IMC的微尺度“组学”分析方法。重债穷国格式非常适合完成拟议的任务。每个项目和核心都严重依赖于计划的其他要素。只有在重债穷国的背景下，我们才能实现协同增效，从规模和业务经济中受益，并将具有不同专业知识的不同调查小组聚集在一个良好和有组织的计划中。

 DESCRIPTION (provided by applicant): The fundamental premise of our application is to provide unbiased, non-hypothesis driven, analysis of immune signatures (IMS) associated with human disease. We will elucidate whether specific IMS are associated with preferential expansion/contraction of certain defined subsets which are already physiologically and homeostatically present within the individual's T cell pool, and which largely maintain their characteristic IMS. We will also consider the alternative, and not mutually exclusive, possibility that changes in IMS reflect generation of distinct T cell subsets with differentiation / activation states uniquely associated with infection, disease and vaccination. Addressing these issues in different human pathogen systems and in different geographical locations, it will be possible to establish to what extent the results obtained are generally applicable. Accordingly, we propose to characterize CD4 and CD8 memory T cell IMS associated with Mycobacterium tuberculosis (MTB) and dengue virus (DENV) in the context of 1) natural immunity and/or control of infection, 2) active and severe disease and 3) administration of licensed or experimental vaccines. Our group has studied MTB and DENV for several years for the following reasons. 1.They are both current global health problems. 2. For these diseases memory T cells are fundamentally associated with protective immunity. 3. Antigen-specific T cell responses are detected in sufficient numbers ex vivo, allowing "omics" study without the need for in vitro expansion or stimulation. 4. Human specimens associated with natural infection/immunity and severe diseases are easily accessible in large numbers. As a result, we have developed a critical mass that is extensively leveraged herein, based on: 1) an established team of experienced LJI investigators, 2) established clinical collaborations with leaders in the field, ensuring that the goal of recruitment of large numbers of suitably characterized individuals will be met (in fact, hundreds of samples are already available), 3) hundreds of epitopes restricted by a variety different HLA class I and II molecules to allow an analysis of memory T cells of unprecedented precision 4) existing data identifying specific T cell subsets as key players in immunity and 5) established and well validated micro- scaled "omics" assays for generating IMC related to MTB and DENV. The HIPC format is ideally suited to accomplish the proposed mission. Each project and core is critically dependent on other elements of the program. Only in the context of HIPC will we be able to realize the synergies, benefit from an economy of scale and operation, and bring different groups of investigators with different expertise together in a well and organized plan.