Mouse Model of Necrotic Tuberculosis Granulomas Develops Hypoxic Lesions
Mouse Model of Necrotic Tuberculosis Granulomas Develops Hypoxic Lesions
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DOI：
10.1093/infdis/jir786
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发表时间：
2012-02-15
影响因子：
6.4
通讯作者：
Jain, Sanjay K.
中科院分区：
文献类型：
--
作者：
Harper, Jamie;Skerry, Ciaran;Jain, Sanjay K.
背景资料。结核病药物的临床前评估通常仅限于小鼠。然而，人类结核病病变的关键特征--坏死和缺氧--在传统的小鼠品系中是缺乏的。我们使用的是C3HeB/FEJ小鼠，它们会因结核分枝杆菌感染而出现坏死性病变。用活体感染动物的正电子发射断层扫描、死后的匹莫硝唑免疫组织化学和细菌基因表达分析来评估C3HeB/FEJ的结核病变是否缺氧。同时评价了PA-824等联合用药在低氧条件下对结核分枝杆菌的治疗效果。C3HeB/FEJ(而不是BALB/c)的结核病变被发现是低氧的，并与已知的低氧相关细菌基因上调有关(P<；.001)。与其他地方报道的在BALB/c小鼠中持续的活性相反，莫西沙星和吡津酰胺(MZ)在C3HeB/FEJ中超过3周没有杀菌作用。尽管PA-824增加了显著的活性，但PA-824和MZ的新组合在C3HeB/FeJ中的疗效不如标准一线方案。我们证明C3HeB/FEJ中的结核病变是低氧的。在C3HeB/FEJ和BALB/c小鼠中，一些关键的结核病药物方案的活性在C3HeB/FEJ和BALB/c小鼠中表现不同。由于C3HeB/FEJ表现出人类结核病的关键特征，该菌株值得作为临床前研究中更具病理学相关性的模型进行评估。
Background. Preclinical evaluation of tuberculosis drugs is generally limited to mice. However, necrosis and hypoxia, key features of human tuberculosis lesions, are lacking in conventional mouse strains.Methods. We used C3HeB/FeJ mice, which develop necrotic lesions in response to Mycobacterium tuberculosis infection. Positron emission tomography in live infected animals, postmortem pimonidazole immunohistochemistry, and bacterial gene expression analyses were used to assess whether tuberculosis lesions in C3HeB/FeJ are hypoxic. Efficacy of combination drug treatment, including PA-824, active against M. tuberculosis under hypoxic conditions, was also evaluated.Results. Tuberculosis lesions in C3HeB/FeJ (but not BALB/c) were found to be hypoxic and associated with up-regulation of known hypoxia-associated bacterial genes (P < .001). Contrary to sustained activity reported elsewhere in BALB/c mice, moxifloxacin and pyrazinamide (MZ) combination was not bactericidal beyond 3 weeks in C3HeB/FeJ. Although PA-824 added significant activity, the novel combination of PA-824 and MZ was less effective than the standard first-line regimen in C3HeB/FeJ.Conclusions. We demonstrate that tuberculosis lesions in C3HeB/FeJ are hypoxic. Activities of some key tuberculosis drug regimens in development are represented differently in C3HeB/FeJ versus BALB/c mice. Because C3HeB/FeJ display key features of human tuberculosis, this strain warrants evaluation as a more pathologically relevant model for preclinical studies.