The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice
The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice
复制标题
DOI：
10.1128/iai.69.12.7711-7717.2001
复制
发表时间：
2001-12-01
影响因子：
3.1
通讯作者：
Chan, J
中科院分区：
文献类型：
--
作者：
Scanga, CA;Mohan, VP;Chan, J
小鼠巨噬细胞通过一氧化氮合酶（NOS2）的诱导异构体产生一氧化氮来发挥有效的抗细菌功能。活性氮中间体（RNI）对结核分枝杆菌感染的保护作用已在各种小鼠实验结核模型中得到很好的证实，这些模型使用实验室结核杆菌菌株通过静脉途径建立感染。然而，关于RNI在宿主防御AL结核中的体内重要性仍然存在重要问题。有一些证据表明，RNI在小鼠肺源性结核杆菌感染后的作用较小，而不是静脉注射。此外，体外研究表明，不同的结核分枝杆菌菌株，包括临床分离株，对RNI抗分枝杆菌作用的易感性差异很大。因此，我们试图严格测试RNI在空气源性和静脉注射感染后对近期临床分离的结核杆菌感染的保护作用。用最近分离的三株独特的结核分枝杆菌感染野生型（wt） C57BL/6和NOS2基因破坏的小鼠。无论感染途径如何，NOS2（-/-）小鼠对结核分枝杆菌的临床分离株或Erdman或H37Rv实验室菌株都比wt小鼠更敏感。分枝杆菌在NOS2（-/-）小鼠器官中的复制水平远高于wt小鼠。尽管临床分离株在NOS2（-/-）小鼠中均表现出增强的毒力，但它们在体内表现出不同的生长速度。本研究提供的结果表明，RNI是控制实验室和临床AL结核菌株引起的小鼠结核感染所必需的。RNI的这种保护作用对于控制由静脉或空气引起的感染至关重要。
Murine macrophages effect potent antimycobacterial function via the production of nitric oxide by the inducible isoform of the enzyme nitric oxide synthase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosis infection has been well established in various murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. However, important questions remain about the in vivo importance of RNI in host defense against AL tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous, M. tuberculosis Infection of mice. Furthermore, in vitro studies have demonstrated that different strains of Al. tuberculosis, including clinical isolates, vary widely in their susceptibility to the anti mycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates of Al. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique H. tuberculosis strains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrupted mice. Regardless of the route of infection, NOS2(-/-) mice were much more susceptible than wt mice to any of the clinical isolates or to either the Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replicated to much higher levels in the organs of NOS2(-/-) mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence in NOS2(-/-) mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the control of murine tuberculous infection caused by both laboratory and clinical strains of AL tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.