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

 描述（由申请人提供）：我们申请的基本前提是提供与人类疾病相关的免疫特征（IMS）的无偏倚、非假设驱动的分析。我们将阐明特定的IMS是否与某些定义的子集的优先扩张/收缩相关，这些子集已经在生理上和体内平衡地存在于个体的T细胞库中，并且在很大程度上保持其特征IMS。我们还将考虑另一种可能性，而不是相互排斥的，IMS的变化反映了分化/活化的不同T细胞亚群的产生 与感染、疾病和疫苗接种有独特关联的状态。在不同的人类病原体系统和不同的地理位置解决这些问题，将有可能确定所获得的结果在多大程度上普遍适用。因此，我们建议在1）天然免疫和/或感染控制，2）活动性和严重疾病和3）许可或实验性疫苗给药的背景下，表征与结核分枝杆菌（MTB）和登革热病毒（DENV）相关的CD 4和CD 8记忆T细胞IMS。我们的小组已经研究了MTB和DENV几年，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细胞从根本上与保护性免疫相关。3.抗原特异性T细胞应答以足够数量离体检测，允许“组学”研究而不需要体外扩增或刺激。4.与自然感染/免疫和严重疾病相关的人体标本很容易大量获得。因此，我们根据以下因素制定了一个临界质量，并在此得到广泛利用：1）由经验丰富的LJI研究人员组成的成熟团队，2）与该领域的领导者建立临床合作，确保达到招募大量适当特征的个人的目标（事实上，已经有数百个样本可用），3）由多种不同的HLA I类和II类分子限制的数百个表位，以允许前所未有的精确度分析记忆T细胞4）现有的数据鉴定特异性T细胞亚群作为免疫中的关键参与者，和5）建立并充分验证的用于产生与MTB和DENV相关的IMC的微尺度“组学”测定。重债穷国倡议的形式非常适合于完成拟议的使命。每个项目和核心都严重依赖于该计划的其他元素。只有在重债穷国倡议的范围内，我们才能够实现协同作用，从规模经济和运作中受益，并将具有不同专门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.