Exit of Mycobacterium avium from granuloma macrophages

非结核分枝杆菌是儿童环境中常见的居民。鸟分枝杆菌是婴幼儿慢性组织感染中最常见的非结核分枝杆菌。从上学开始，M。禽流感通常影响患有基础疾病的人，例如免疫缺陷综合征或慢性肺病。M.禽流感病毒主要感染巨噬细胞（Mac），巨噬细胞（Mac）作为确定的种类，如巨细胞和上皮样细胞，导致称为肉芽肿的组织化组织反应。肉芽肿相对于驻留和进入的免疫细胞以及感染单个细胞的分枝杆菌的发展是高度动态的，并且对于分枝杆菌遏制和免疫介导的病理学都是至关重要的。在本研究中，M.将在体外和小鼠感染模型中分析从确定的Mac和祖物种中排出的禽流感病毒，以测试以下模型：M.禽流感病毒主要通过驱动宿主组织的细胞凋亡而退出受感染的宿主组织。凋亡的Mac被传入的Mac祖细胞转化为巨细胞。这允许肉芽肿生长/成熟，并且局部M. avium持久性。特定病灶位于解剖M上。禽流感诱导的细胞死亡，特别是细胞凋亡，作为一个关键的退出机制，分枝杆菌用来破坏Mac免疫，细胞间细菌转移和驱动相对容许的肉芽肿的形成。另一个重点将是Mac的起源和分化状态，即急性骨髓源性和祖细胞样，相对于或组织驻留完全位点适应，如何确定退出途径，以及分枝杆菌适应细胞内环境。为了实现这些目标，我们将结合联合收割机在体外模型与命运定位，转录组分析，高分辨率成像和过继细胞转移。

Non-tuberculous mycobacteria are common inhabitants in the environment of children. Mycobacterium avium is the most frequently isolated non-tuberculous mycobacterial species in chronic tissue infections in infants and toddlers. From school age onwards, M. avium infections usually affect people with underlying diseases, e.g. immunodeficiency syndromes or chronic lung disease. M. avium predominantly infects macrophages (Mac), which contribute, as defined species like giant and epitheloid cells, to organized tissue reactions called granulomas. The development of granulomas with respect to resident and incoming immune cells, as well as mycobacteria infecting individual cells, is highly dynamic and crucial for both mycobacterial containment and immune mediated pathology. In this proposal, mechanisms of M. avium exit from defined Mac and progenitor species both in vitro and in mouse infection models will be analyzed, in order to test the following model: M. avium exits primarily infected resident tissue Macs by driving them into apoptosis. Apoptotic Mac are the taken up by incoming Mac progenitors transforming into giant cells. This allows for granuloma growth/maturation, and local M. avium persistence. Specific foci will lie on dissecting M. avium-induced cell death, in particular apoptosis, as a key exit mechanism, which mycobacteria use to subvert Mac immunity, for intercellular bacterial transfer and to drive formation of relatively permissive granulomas. Another focus will be on how the Mac origin and differentiation state, i.e. acutely bone marrow-derived and progenitor like, versus or tissue resident fully site adapted, determine exit pathways, as well as mycobacterial adaptation for the intracellular environment. To achieve these goals, we will combine in vitro models with fate mapping, transcriptome analysis, high resolution imaging and adoptive cell transfer.