Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ
Mycobacteria lacking the RD1 region do not induce necrosis in the lungs of mice lacking interferon-γ
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DOI：
10.1111/j.1365-2567.2006.02427.x
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发表时间：
2006-10-01
期刊：
影响因子：
6.4
通讯作者：
Orme, Ian M.
中科院分区：
文献类型：
--
作者：
Junqueira-Kipnis, Ana Paula;Basaraba, Randall J.;Orme, Ian M.
最近假设结核分枝杆菌中的差异基因区域 1 (RD1) 编码对自然界中的宿主细胞具有细胞毒性的蛋白质。我们在这里证明，虽然结核分枝杆菌在无法产生干扰素-γ (IFN-gamma) 的基因破坏小鼠 (GKO) 的肺部逐渐生长，但用牛分枝杆菌卡介苗 (BCG) 感染的类似小鼠在大约 20 天后可重复地表现出疾病明显减缓。对感染 BCG 的 GKO 小鼠进行仔细检查，发现肺部出现严重的肉芽肿性炎症，而感染结核分枝杆菌的类似小鼠则表现出大规模进行性坏死。在感染 BCG 的 GKO 小鼠中，大量激活的效应 T 细胞（其中一些对细胞因子肿瘤坏死因子呈强阳性）以及激活的自然杀伤细胞在肺部积聚。为了进一步检验观察到的差异与 RD1 区域缺失直接相关的假设，随后发现，缺乏 RD1 的结核分枝杆菌突变体在正常小鼠和 GKO 小鼠中均逐渐生长，但未能在任一动物中诱导任何程度的坏死，尽管在肺部达到相似的水平。然而，当小鼠感染这种突变体（其中RD1区域已通过互补恢复）时，肺部再次发生大规模坏死。这些数据支持这样的假设：RD1 区域编码的蛋白质是坏死的主要原因，并且对疾病的发病机制有显着贡献。
The genetic region of difference 1 (RD1) in Mycobacterium tuberculosis has recently been hypothesized to encode for proteins that are cytotoxic to the host cell in nature. We demonstrate here that while M. tuberculosis grew progressively in the lungs of gene disrupted mice (GKO) unable to produce interferon-gamma (IFN-gamma), similar mice infected instead with M. bovis bacillus Calmette-Guerin (BCG) reproducibly exhibited an obvious slowing of the disease after about 20 days. Closer examination of BCG-infected GKO mice showed a florid granulomatous inflammation in the lungs, whereas similar mice infected with M. tuberculosis exhibited wholesale progressive necrosis. In the BCG-infected GKO mice large numbers of activated effector T cells, some strongly positive for the cytokine tumour necrosis factor, as well as activated natural killer cells accumulated in the lungs. To further test the hypothesis that the differences observed were directly associated with the loss of the RD1 region, it was then shown that a mutant of M. tuberculosis lacking RD1 grew progressively in both normal and GKO mice but failed to induce any degree of necrosis in either animal despite reaching similar levels in the lungs. However, when mice were infected with this mutant, in which the RD1 region had been restored by complementation, wholesale necrosis of the lungs again occurred. These data support the hypothesis that proteins encoded in the RD1 region are a major cause of necrosis and contribute significantly to the pathogenesis of the disease.