Schematic illustration of the phagocyte responses to the bacterial pathogens M. marinum(A), M. leprae(B), B. cenocepacia(C), and S. aureus(D). (A) Macrophages phagocytose M. marinum (1) and release ESAT-6 (2). ESAT-6-driven Mmp9 production by epithelial cells leads to macrophage recruitment (3) and granuloma formation (4). Newly-arriving macrophages become infected by engulfing dying infected macrophages (5). Infected macrophages can establish secondary granulomas (6). Low TNF levels promote intracellular bacterial growth and macrophage necrosis (7). High TNF levels promote mROS production within infected macrophages that, although initially bactericidal, also leads to necrosis (8). Necrosis results in the release of bacteria into the extracellular milieu (9). Neutrophils can phagocytose infected macrophage debris (10) and kill M. marinum by NADPH oxidase-mediated ROS production and Hif-1α-dependent reactive nitrogen species production (11). (B)M. leprae-infected macrophages migrate along nerve axons (1), where PGL-1 (2) stimulates iNOS-driven nitric oxide production in macrophages (3) that damages mitochondria in adjacent axons (4). (C) Following i.v. delivery, macrophages phagocytose B. cenocepacia (1) providing a replication niche (2). Infected macrophages produce Il1b (3) that attracts neutrophils and macrophages (4), leading to tissue damage resulting from degranulating neutrophils (5). The inflammatory response also leads to myeloid cell ablation that favors the survival of infected macrophages (6). B. cenocepacia can disseminate through non-lytic escape from infected macrophages (7). Following s.c. infection, neutrophils phagocytose B. cenocepacia (8) but are inefficient in killing the bacteria and instead release the bacteria into the extracellular milieu (9). (D) Following phagocytosis of S. aureus by neutrophils (1), NADPH oxidase activity (2) contributes to the formation of non-acidic Lc3-positive phagosomes (3) that provide a replication niche. Phagosome membrane damage results in the release of bacteria into the cytosol (4), neutrophil death and bacterial dissemination (5).
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