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Ulrich E. Schaible (2011-2017)

The phagosomal fate of Mycobacterium tuberculosis-infected dying/dead cells

Efferocytosis is the guarding mechanism to remove dying/dead cells from tissues during growth and remodelling and is executed primarily by macrophages (MO) and polymorphonuclear neutrophils (PMN). During infection with the tuberculosis (TB) agent, Mycobacterium (M.) tuberculosis, large numbers of cells usually involved in host defense succumb to cell death. These cells have to be removed to limit tissue damage and inflammation. As these cells are also parasitized by intracellular mycobacteria now loosing their host niches to cell death, the need to contain the infection makes efferocytosis an essential process during the host response to M. tuberculosis, though not well studied yet. M. tuberculosis is a facultative intracellular pathogen abusing phagocytes for survival and proliferation depending on the cell type entered, i.e. short lived PMN vs. long lived MO. We found that infection with virulent mycobacteria, drive PMN, the predominant host cells in active TB, quickly into necrotic cell death induced by the PMN's own reactive oxygen intermediates (ROI). In contrast, attenuated M. tuberculosis strains lacking the RD1 genomic virulence region extend survival of PMN before apoptotic suicide eventually kills attenuated mycobacteria in a ROI dependent manner. Virulence-associated escape of mycobacteria from killing by PMN targets them to PMN- or MO-derived efferocytes. We observed distinct intracellular fate and responses upon efferocytosis of apoptotic vs. necrotic cell-derived mycobacteria-containing material. We will further analyse the molecular basis for M. tuberculosis-induced necrotic cell death in PMN and the consequences for efferocytosed mycobacteria. Therefore, we study molecular targets of mycobacteria in PMN, molecules involved in downstream intracellular fate upon efferocytosis by MO and PMN and how mycobacterial virulence factors determine this process. We expect novel insights into mycobacterial fate in mixed host cell populations with respect to pathogen survival and elimination.