Analysis for regulatory mechanism of macrophage functions by Mycobacterium tuberculosis

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In the series of study, we investigated how Mycobacterium tuberculosis modulates cell death of macrophages and the cytokine production. A virulent H37Rv triggers necrosis of infected macrophages. It is supposed that the bacterium ultimately escapes macrophages by induction of necrosis. At the initial phase of infection, however, H37Rv avoids excessive necrosis of infected host cells through induction of caspase-9 activation. It has been shown that RD1 locus in genome of M. tuberculosis is involved in the virulence of bacteria and the necrosis-inducing ability. We found that RD1 appears to encode some components possibly playing a role in the induction of host cell necrosis by inducing damage of the mitochondrial inner membrane and causing ATP depletion. In addition, we found that M tuberculosis phagocytosed in macrophages appears to keep active metabolism inside cells and some metabolites but not structural components of bacteria trigger the production of cytokines that are important for development of Th1 cells. Furthermore, we focused on the interaction between M tuberculosis and alveolar epithelial cells because the cells play a role in the first-line of defense by producing chemokines and cytokines in the lung. Results showed that the interaction of cells with Mycobacterial mammalian cell entry protein 1A (Mce1A) that play a critical role in invasion of bacteria into cells did not induce production of chemokines. However, it may promote chemokine induction by augmenting the interaction between bacteria and epithelial cells.