Exploring the impact of inflammaging on immune function during M. tb infection

 描述(申请人提供)：老龄化是发展原发结核病和将潜伏的结核分枝杆菌感染转化为活动性结核病的主要风险因素。因此，65岁以上的人结核病发病率最高，最容易发生与结核病相关的死亡。导致老年人对结核病易感性增加的免疫学因素在很大程度上仍不清楚。该计划项目的主要假设是，炎症途径的特定变化(称为炎症)在衰老过程中调节了肺和系统免疫中独特的和次优的重新编程，并恶化了老年人感染结核分枝杆菌的结果。项目1将分析肺表面活性物质和补体如何促进老化肺内肺泡复杂性的减少，并修改最初与结核分枝杆菌的细胞相互作用。项目2将讨论与年龄相关的肺泡巨噬细胞功能的变化及其如何影响结核分枝杆菌感染。项目3将确定衰老和炎症对控制老年小鼠原发和潜伏的结核分枝杆菌感染的影响。项目4将调查患有潜伏期或活动期结核病的老年受试者中结核分枝杆菌特异性单核细胞和T细胞的功能。总之，这些研究将提供机制信息，以了解炎症和免疫衰老如何影响老年人的结核分枝杆菌感染。该项目汇集了一批在临床结核病、结核病发病机制和对感染的免疫反应方面具有专业知识的合作科学家，后者在人类和动物模型中都有。

 DESCRIPTION (provided by applicant): Aging is a major risk factor for both the development of primary tuberculosis (TB) disease and for the conversion of latent Mycobacterium tuberculosis (M.tb) infection to active TB disease. As a consequence, persons over the age of 65 have the highest TB case rate and are the most susceptible to TB associated death. The immunological factors that contribute to the increased susceptibility of the elderly to TB remain largely unknown. The overarching hypothesis of this program project is that specific changes in inflammatory pathways (termed inflammaging) mediate unique and sub-optimal re-programming in pulmonary and systemic immunity during aging, and worsen the outcome of M.tb infection in the elderly. Project 1 will analyze how pulmonary surfactant and complement contribute to the loss of alveolar complexity within the aging lung and modify the initial cellular interaction with M.tb. Project 2 will address age-associated changes in the function of alveolar macrophages and how they affect M.tb infection. Project 3 will determine the impact of aging and inflammaging on control of primary and latent M.tb infection in old mice. Project 4 will investigat M.tb specific monocyte and T cell function in elderly subjects with latent or active TB. Altogether, these studies will provide mechanistic information to understand how inflammaging and immune senescence impact M.tb infection in the elderly. The program brings together an established group of collaborative scientists with expertise in clinical TB, TB pathogenesis and the immune response to infection, the latter both in human and animal models.