Escape mechanisms of intracellular bacteria and the analysis of protective immunity and tissue damage in the infected host

本研究的目的之一是研究细胞内细菌的逃逸机制及其在感染宿主诱导细胞免疫(CMI)中的作用。此外，我们希望从T细胞功能和识别抗原方面分离保护性T细胞和参与组织损伤的T细胞。在利用小鼠感染模型的实验中，获得了以下结果。HLYA编码的LLO(李斯特菌素O)在单核细胞增多性李斯特菌逃逸过程中起重要作用。LIO除了对细胞膜起主要作用外，还能在巨噬细胞中诱导多种细胞因子。2.只有那些能够表达hlya诱导CMI的李斯特氏菌株才能通过诱导宿主体内IL-1α和干扰素-γ来诱导T细胞的功能发育。3.Th1型CD4^+T细胞以抗原特异性方式产生大量的干扰素-γ，从而发挥保护性免疫作用。产生干扰素-γ能力较差的CD4+T细胞仅表达迟发性超敏反应。4.保护性T细胞识别单核细胞增多性李斯特氏菌的多种抗原，而卡介苗反应性干扰素-γ产生的CD4^+T细胞主要识别18-20 kDa的抗原。结核病患者的外周血淋巴细胞对这种特殊的抗原表现出良好的反应，从而产生干扰素-γ。5.单核细胞增多性李斯特氏菌感染宿主产生的CD8~+T细胞可能通过产生肿瘤坏死因子6而导致组织损伤。在感染宿主产生的多种非特异性细胞因子中，NK细胞来源的干扰素-γ在诱导型一氧化氮合酶(INOS)的表达中起着至关重要的作用，是活体细菌感染所特有的。

One of the purpose of this study was to study the escape mechanisms of intracellular bacteria and its contribution to the induction of cell-mediated immunity (CMI) in infected hosts. In addition, we wanted to segregate the protective T cells and those involved in tissue damage with respect to T cell function and antigen in recognition. The following results were obtained in the experiments using murine models of infection.1. LLO (listeriolysin O) encoded by hlya plays a crucial role in the escape of Listeria monocytogenes. LLO is capable of inducing various cytokines in macrophages in addition to its primary effect on cell membrane. 2. Only those strain of Listeria capable of expressing hlya induce CMI.LLO appeared to induce the functional development of T cells through its ability to induce IL-1alpha and IFN-gamma in the host. 3. Protective immunity is exerted by Th1 type CD4^+ T cells by producing a qreat amout of IFN-gamma in an antigen-specific manner. CD4^+ T cells with poor ability to produce IFN-gamma were only active in expression of delayd-type hypersensitivity. 4. Protective T cells recognize a wide range of antigens in L.monocytogenes, while BCG-reactive IFN-gamma-producing CD4^+ T cells recognize mainly 18 to 20kDa antigen. Peripheral blood lymphocytes from tuberculous patients showed a good response against this particular antigen resulting in IFN-gamma production. 5. CD8^+ T cells generated in L.monocytogenes-infected host seemed to contribute to tissue damage through production of TNF.6. Among various cytokines which are non-specifically produced in infected host, NK cell-derived IFN-gamma was critically important in the expression of iNOS (inducible NOS) and was unique to viable bacterial infection.