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，据估计，结核病是全球主要的死亡原因。 死亡率的很大一部分是由于与其他地方性感染合并感染导致细胞免疫力减弱。 抗分支杆菌免疫主要由CD 4 + T细胞介导，它调节保护性肉芽肿性炎症的形成，以限制病原体传播并保护周围健康组织。 我们建议使用小鼠慢性结核模型，M。牛卡介苗rin（BCG），以检查用流感病毒和真菌荚膜组织胞浆菌（Histoplasma capsulatum）双重感染的效果。 我们将用不同的充分表征的T细胞表位对BCG和继发性病原体进行遗传标记。 使用表位特异性II类四聚体染色试剂，我们可以通过肉芽肿细胞的流式细胞术分析来跟踪对BCG或继发性病原体特异性的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细胞相互作用（帮助，抑制，竞争）已与标称抗原，我们的研究将集中在两个传染性病原体的T细胞反应如何相互干扰。 我们打算通过用全谱的T细胞感染动物来进行观察（B10.BR），感染B10.BR动物，其中对两个表位特异性的TCR转基因T细胞群已作为哨兵过继转移，以及在过继转移TCR转基因T细胞后感染免疫缺陷型Rag 2-/-，所述TCR转基因T细胞对由所述感染因子表达的表位标签具有特异性，以构建小T-手机网络 因此，我们可以非常精确地研究具有分枝杆菌特异性的肉芽肿细胞和对其他感染具有特异性的肉芽肿细胞的募集和功能质量。 本研究的目的是了解控制不同感染的T细胞反应的相互作用。 希望这将导致更好的治疗分枝杆菌疾病。

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.