Mouse models for TB infection across the lifespan

描述（由申请人提供）：结核分枝杆菌（Mtb）继续在世界范围内引起显著的发病率和死亡率。老年人的结核病可直接由新的感染引起，这反映了有记载的老年人对包括结核分枝杆菌在内的多种感染的易感性普遍增加，或从以前潜伏的结核分枝杆菌感染中重新激活，并且通常归因于适应性免疫功能的缺陷。然而，很少有实验信息来定义免疫功能障碍的具体方面，这些方面导致老年人对结核杆菌感染的易感性增加。随着年龄的增长，中枢免疫功能（胸腺产生T细胞）、外周T细胞库和功能参数以及外周环境（例如炎症状况增加）发生了许多变化，这些变化中的任何一个或全部都可能导致老年人活动性结核杆菌感染的风险增加。然而，每种机制最好以不同的方式治疗。因此，我们的长期目标是确定这些免疫变化对老年人结核杆菌感染率上升的具体贡献，并制定有效的治疗策略。在本提案中，我们将使用Manley实验室开发的独特小鼠遗传资源来测试两个假设：这种先天样的TEM亚群在遗传过程中起关键作用

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) continues to cause significant morbidity and mortality worldwide. TB in the elderly can arise directly from a new infection, reflecting the documented general increase in susceptibility of the elderly to numerous infections including Mtb, or reactivate from a previously latent Mtb infection, and is frequently attributed to deficits in adaptive immune function. However, little experimental information exists to define the specific aspects of immune dysfunction that contribute to the increased susceptibility of the elderly to Mtb infection. There are numerous changes in central immune function (thymus production of T cells), peripheral T cell repertoire and functional parameters, and in the peripheral environment (e.g. increased inflammatory conditions) with aging, any or all of which could contribute to the increased risk for active Mtb infection in the elderly. However, each of these mechanisms would be best approached therapeutically in different ways. Thus, our long-term goal is to identify the specific contributions of these immune changes to increased rates of Mtb infection in the elderly and develop effective treatment strategies. In this proposal, we will use unique mouse genetic resources developed in the Manley lab to test two hypotheses: that this innate-like TEM subpopulation plays a critical role in controlling Mtb infection and establishing latency, and that time since thymic involution plays a significant role in enhanced rates of Mtb primary infections and latency reactivation in the elderly. In Aim 1 we will determine whether innate-like TEM peripheral T cells can enhance the immune response to primary Mtb infection, using the Foxn1�/� mouse model and in vitro and in vivo assays. In Aim 2 we will test whether enhanced disease progression and severity of active Mtb infection in the elderly is due to changes in the peripheral T cell pool caused by thymic involution, or by the physiological effects of aging using Foxn1Z/Z mice that undergo premature thymic involution. These studies may provide new insights into the T cell mechanisms regulating Mtb infection in the elderly, and define new mouse models that may be useful for the study of the immune response to Mtb infection.