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Cell Death in Tuberculosis

After inhalation, Mycobacterium tuberculosis (Mtb) invades alveolar macrophages to establish infection in the host. A key to Mtb virulence is its ability to inhibit phagosome maturation, creating a niche that supports intracellular bacillary replication. We previously discovered that macrophages may respond to low-multiplicity infection with attenuated Mtb complex strains by undergoing tumor necrosis factor-alpha (TNF)-mediated apoptosis, while virulent bacilli evade that response (Keane et al. Infect. Immun. 65:298). Apoptosis provides an innate host defense function analogous to its well studied role in defense against viruses. Consistent with that model, we and others found that virulent Mtb strains express anti-apoptotic functions that act to preserve host cell viability. Macrophage apoptosis may contribute to host defense in TB by direct microbicidal mechanisms in the dying cell and by packaging bacilli in apoptotic bodies that, following efferocytosis by naive macrophages, delivers the bacteria to a killing phagolysosome. Efferocytosis has also been shown by other to promote priming of adaptive immunity by dendritic cells.

Having found that virulent Mtb strains inhibit apoptosis at low MOI to preserve their replication sanctuary, we questioned how such strains exit the macrophage when its usefulness is expended. This work resulted in the discovery that at a threshold ~25 bacilli per macrophage, virulent (and certain attenuated) Mtb strains trigger a unique caspase- and TNF-independent mode of macrophage cell death (Lee et al. J. Immunol. 176:4267). Macrophages dying with a high Mtb load have initial features of apoptosis that rapidily progress to necrosis without reducing Mtb viability. This "burst size" cytolytic activity of Mtb requires viable, intracellular Mtb and it is markedly diminished by mutation of Mtb phoPR but it does not require Esx-1 (Lee et al. PLoS One 6:e18367). Dying cells exhibit nuclear condensation without fragmentation and widespread damage to mitochondrial, nuclear and outer cell membranes, consistent with attack by lipases that may be of host or bacterial origin. Current work on this project is investigating the relevance of our in vitro data to events occurring in the lung after aerosol Mtb challenge.