Exit of Mycobacterium avium from granuloma macrophages

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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.