Analysis for regulatory mechanism of macrophage functions by Mycobacterium tuberculosis

本系列研究探讨了结核分枝杆菌如何调节巨噬细胞的死亡和细胞因子的产生。致命的H37 Rv引发感染的巨噬细胞坏死。据推测，细菌最终通过诱导坏死而逃离巨噬细胞。然而，在感染的初始阶段，H37 Rv通过诱导半胱天冬酶-9活化来避免感染的宿主细胞的过度坏死。结果表明，M.结核病涉及细菌的毒力和坏死诱导能力。我们发现RD 1似乎编码一些成分，这些成分可能通过诱导线粒体内膜损伤并导致ATP耗尽而在诱导宿主细胞坏死中发挥作用。此外，我们还发现巨噬细胞吞噬的结核分枝杆菌似乎在细胞内保持活跃的代谢，并且一些代谢产物而不是细菌的结构成分触发了对Th 1细胞发育重要的细胞因子的产生。此外，我们专注于结核分枝杆菌和肺泡上皮细胞之间的相互作用，因为这些细胞通过在肺中产生趋化因子和细胞因子在第一线防御中发挥作用。结果表明，细胞与分枝杆菌哺乳动物细胞进入蛋白1A（Mce 1A）的相互作用，在细菌侵入细胞中发挥关键作用，不诱导产生趋化因子。然而，它可能通过增强细菌和上皮细胞之间的相互作用来促进趋化因子的诱导。

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.