Molecular mechanism of macrophage activation and intracellular parasitism by intracellular parasitic bacteria

(1)李斯特菌溶血素0(Listeriolysin 0，LLO)是单核细胞增生性李斯特氏菌的主要毒力因子，除在宿主巨噬细胞内通过溶细胞活性逃逸外，还具有较强的细胞因子诱导活性。我们的研究表明，细胞因子诱导活性，尤其是干扰素诱导活性依赖于N-末端，而杀伤活性依赖于C-末端。(2)研究表明，所有细胞因子诱导的CDC家族蛋白，包括LW-FIbt，都能激活巨噬细胞IL-12和IL-18。这些巨噬细胞衍生的细胞因子反过来刺激NK细胞产生γ干扰素，这是诱导Th1依赖的保护性免疫所必需的。(3)塞利格里李斯特菌和伊万诺维李斯特菌产生的LLO和相关蛋白在细胞因子诱导能力上存在显着差异。我们能够证明这种差异高度依赖于N-末端结构域的结构差异。巨噬细胞胞浆中识别LLO的独特分子也起到了作用。(4)结核分枝杆菌诱导Th1细胞因子需要活菌的刺激。在小鼠变态反应实验模型中，LLO和具有Th1细胞因子诱导活性的相关蛋白对变态反应的缓解和控制是有效的。

(1) Listeriolysin 0 (LLO) is the major virulence factor of Listeria monocytogenas a representative intracellular parasitic bacteria, and exhibits a strong cytokine-inducing activity in addition to its role for the escape of this bacterium by cytolytic activity in the host macrophaes. Our study dearly showed that the cytokine-inducing activity, especially gammainterferon-inducing activity is dependent on the N-terminus while the cytolytic activity depends on the C-terminus(2) It was shown that all the cytokine-inducing CDC family proteins including LW filbt activate macrophages far IL-12 and IL-18 and. these macrophage-derived cytokines in turn stimulate NK cells for gamma interferon production that is essential for the induction of Thl-dependent protective immunity(3) There is a significant difference in the cytokine-inducing ability among LLO and allied proteins produced by Listeria seeligeri and Listeria ivanovii. We were able to show that such a difference is highly dependent on the structural difference at the N-terminus domain. A contribution of unique molecule recognizing LLO inside macrophage cytosol was also suggested.(4) Thl cytokine induction by Mycobacterium tuberculosis requires the stimulation with viable bacteria. It was shown that some growing bacteria-derive factor that depends on bacterial metabolism is required.(5) In experimental model of allergic condition in mice, LLO and allied protein with Thl cytokine-inducing activity were effective for the alleviation and control of allergic response.