Identification of nitric oxide synthase as a protective locus against tuberculosis
Identification of nitric oxide synthase as a protective locus against tuberculosis
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DOI：
10.1073/pnas.94.10.5243
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Nathan, CF
中科院分区：
文献类型：
--
作者：
MacMicking, JD;North, RJ;Nathan, CF
宿主免疫系统的诱变有助于确定对抗结核病所必需的反应途径。一些这样的途径可能作为一个共同的保护基因的激活剂：诱导型一氧化氮合酶（NOS2）。在这里，我们提供了直接的证据，证明该基因控制结核分枝杆菌的原发性感染，使用小鼠纯合的NOS2等位基因中断。NOS2（-/-）小鼠被证明是高度敏感的，类似于被高剂量糖皮质激素免疫抑制的野生型幼崽，并且允许结核分枝杆菌在肺部复制的速度比其他基因缺陷宿主更快。易感性似乎独立于唯一已知的自然遗传抗微生物位点NRAMP1。通过给药N-6-（1-亚氨基乙基）- l -赖氨酸特异性抑制NOS2可加速野生型小鼠慢性结核的进展。总之，这些发现确定NOS2是结核的关键宿主基因。
Mutagenesis of the host immune system has helped identify response pathways necessary to combat tuberculosis. Several such pathways may function as activators of a common protective gene: inducible nitric oxide synthase (NOS2). Here we provide direct evidence for this gene controlling primary Mycobacterium tuberculosis infection using mice homozygous for a disrupted NOS2 allele. NOS2(-/-) mice proved highly susceptible, resembling wild-type littermates immunosuppressed by high-dose glucocorticoids, and allowed Mycobacterium tuberculosis to replicate faster in the lungs than reported for other gene-deficient hosts. Susceptibility appeared to be independent of the only known naturally inherited antimicrobial locus, NRAMP1. Progression of chronic tuberculosis in wild-type mice was accelerated by specifically inhibiting NOS2 via administration of N-6-(1-iminoethyl)-L-lysine. Together these findings identify NOS2 as a critical host gene for tuberculostasis.