Doherty T M, Sher A
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1997 May 15;158(10):4822-31.
To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.
为了研究细胞介导的免疫在控制鸟分枝杆菌感染中的作用，我们研究了T淋巴细胞依赖性、巨噬细胞介导的反应成分中的靶向基因破坏对小鼠抵抗这种病原体的影响。正常小鼠发生慢性无症状感染，脾脏、肝脏和肺中IFN-γ、IL-12和TNF-α的mRNA迅速诱导。在感染的前4周，基因敲除小鼠、重度联合免疫缺陷（scid）小鼠和野生型小鼠的细菌载量没有差异。然而，感染后8周，与野生型对照相比，scid小鼠以及IFN-γ基因靶向破坏的动物显示出细菌生长增强。相反，缺乏TNF-α p55/p75受体基因或诱导型一氧化氮合酶基因的敲除小鼠不仅细菌载量与野生型动物相当，而且它们也没有表现出感染的野生型对照中明显的脾肿大和丝裂原诱导的淋巴细胞增殖反应的深度抑制。因此，鸟分枝杆菌明显不同于其他细胞内病原体（如单核细胞增生李斯特菌、弓形虫和结核分枝杆菌），后者在宿主中的初始复制受到Th1依赖性效应机制的严格控制。相反，宿主细胞介导的免疫的主要作用是在感染的慢性期限制细菌生长。令人惊讶的是，诱导型一氧化氮对免疫病理学似乎比对这种细菌病原体诱导的宿主抵抗力更重要。
