Mycobacterium tuberculosis, the classic intracellular pathogen that causes the chronic disease tuberculosis, enters cells — usually macrophages — by endocytosis, and then arrests the development of the phagosome so that it doesn't fuse with lysosomes and acidify. Bacilli replicate inside this modified compartment, hidden from immune surveillance by antibody and complement. Glycoconjugates released by the intracellular bacilli help to induce and maintain the granuloma — a tissue response that limits bacterial spread but ensures persistence of the infection. Compared with M. tuberculosis, M. marinum can also result in latent long-term infections with associated granuloma formation, but has a much shorter generation time. In addition, it can be safely studied using ordinary laboratory facilities and has multiple animal-infection models. Studying M. marinum therefore might provide answers to some of the unresolved questions about M. tuberculosis pathogenesis.
During painstaking scrutiny using time-lapse video microscopy of the phagosome maturation process following infection with M. marinum, Stamm et al. noticed that while most of the bacilli were in membrane-bound phagosomes, some bacilli were motile in the cytoplasm and had dense tails of polymerized actin. Importantly, other well-studied intracellular bacterial pathogens, including Listeria monocytogenes, Shigella flexneri and Rickettsia rickettsii, can escape from phagosomes and use actin-based motility to move through the cytoplasm and spread from cell-to-cell. By 48 hours post-infection, as many as 20% of the intracellular bacilli had exited the phagosome and become motile. Most infected cells eventually contained some motile bacilli, which were always located in the cytoplasm. Listeria and Shigella use tactics that have evolved independently to polymerize host-cell actin, and this study showed that M. marinum uses a mechanism most similar to that used by Shigella. Single motile cells were tracked and were seen to exit one cell and enter a neighbouring cell using polymerized actin, in a macrophage monolayer. Clear evidence that this is biologically relevant was obtained by visualizing the spread of fluorescently labelled bacilli in an infected monolayer — bacilli were able to infect neighbouring cells and spread, even when extracellular bacteria were killed with a broad-spectrum antibiotic.
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