Secondary infections during mycobacterial disease

描述（由申请人提供）：世界上大约30%的人口感染了结核分枝杆菌，结核病已被估计为世界范围内死亡的主要原因。其中很大一部分死亡是由于与其他地方性感染合并感染而导致细胞免疫力减弱。抗分枝杆菌免疫主要由CD4+ T细胞介导，其调节保护性肉芽肿炎症的形成，以限制病原体的传播并保护周围的健康组织。我们提出用慢性结核小鼠模型，牛分枝杆菌卡介苗（BCG），研究流感病毒和真菌荚膜组织原体超感染的影响。我们将用不同的特征良好的T细胞表位对卡介苗和继发病原体进行遗传标记。利用表位特异性的ⅱ类四聚体染色试剂，通过流式细胞术分析肉芽肿细胞，我们可以跟踪BCG或继发性病原体特异性tcr群体的定位和表型。该模型还将用于检查超感染对器官负荷的影响，不同tcr特异性T细胞群产生保护性细胞因子的能力，以及与局部抗原特异性相关的基因表达变化。T细胞的相互作用（帮助、抑制、竞争）已经被描述为名义抗原，我们的研究将集中在T细胞对两种感染因子的反应如何相互干扰。我们打算通过用全谱T细胞（B10）感染动物来进行观察。BR)，感染B10。将两种表位特异性的TCR转基因T细胞群过继转入BR动物作为哨兵，并在过继转入感染因子表达的表位标签特异性的TCR转基因T细胞后感染免疫缺陷的Rag2-/-，构建一个小的T细胞网络。因此，我们可以非常精确地研究具有分枝杆菌特异性和其他感染特异性的肉芽肿细胞的募集和功能质量。

DESCRIPTION (provided by applicant): Approximately 30% of the world's population has been infected with Mycobacterium tuberculosis, and tuberculosis has been estimated to be the leading cause of death worldwide. A significant fraction of that mortality is from weakened cellular immunity due to co-infection with other endemic infections. Anti-mycobacterial immunity is mediated primarily by CD4+ T cells, which regulate the formation of protective granulomatous inflammation to restrict pathogen dissemination and protect surrounding healthy tissue. We propose to use a mouse model of chronic tuberculosis, M. bovis strain bacille Calmette Gurin (BCG), to examine the effect of super-infection with influenza virus and the fungus Histoplasma capsulatum. We will genetically mark both the BCG and secondary pathogen with different well-characterized T cell epitopes. Using epitope specific class ll tetramer staining reagents, we can follow the localization and phenotype of TCR-populations specific for either BCG or the secondary pathogen by flow cytometric analysis of granuloma cells. This model will also be used to examine the effect of super-infection upon organ load, the capacity of different TCR-specific T cell populations to produce protective cytokines, and gene-expression changes associated with local antigenic specificity. T cell interactions (help, suppression, competition) have been described with nominal antigens, and our studies will focus on how T cell responses for two infectious agents interfere with each other. We intend to make our observations by infecting animals with a full spectrum of T cells (B10.BR), infecting B10.BR animals into which TCR transgenic T cell populations specific for both epitopes have been adoptively transferred as sentinels, and infecting immunodeficient Rag2-/- after adoptive transfer of TCR transgenic T cells that are specific for the epitope tags expressed by the infectious agents to construct a small T-cell network. Thus we can very precisely study the recruitment and functional qualities of granuloma cells having mycobacterial specificity and those with specificity for other infections. The goal of this research is to understand the interaction of T cell responses controlling different infections. Hopefully, this will lead to better treatments of mycobacterial disease.