Mouse models for TB infection across the lifespan

描述（由申请方提供）：结核分枝杆菌（Mtb）继续在全球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感染引起，反映了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，或从先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，很少有实验信息存在，以确定免疫功能障碍的具体方面，有助于增加老年人对结核分枝杆菌感染的易感性。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，其中任何一种或所有变化都可能导致老年人活动性Mtb感染风险增加。然而，这些机制中的每一个都将以不同的方式得到最好的治疗。因此，我们的长期目标是确定这些免疫变化对老年人结核病感染率增加的具体贡献，并制定有效的治疗策略。在这项提议中，我们将使用曼利实验室开发的独特小鼠遗传资源来测试两个假设：这种先天的TEM亚群在人类基因组中起着关键作用。 控制Mtb感染和建立潜伏期，胸腺退化的时间在老年人中Mtb原发感染率和潜伏期再激活率的提高中起着重要作用。在目标1中，我们将使用Foxn 1 <$/<$小鼠模型和体外和体内测定来确定先天性TEM外周T细胞是否可以增强对原发性Mtb感染的免疫应答。在目标2中，我们将测试老年人活动性Mtb感染的疾病进展和严重程度的增强是否是由于胸腺退化引起的外周T细胞池的变化，或者使用经历过早胸腺退化的Foxn 1 Z/Z小鼠老化的生理效应。这些研究可能为调节老年人Mtb感染的T细胞机制提供新的见解，并定义新的小鼠模型，可能有助于研究Mtb感染的免疫反应。

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.