DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions
DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions
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DOI：
10.1165/rcmb.2014-0230oc
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发表时间：
2015-06-01
影响因子：
6.4
通讯作者：
Kaushal, Deepak
中科院分区：
文献类型：
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作者：
Gautam, Uma S.;McGillivray, Amanda;Kaushal, Deepak
结核分枝杆菌（Mtb）必须抵抗肉芽肿内的缺氧才能持续存在。DosR与感受器激酶DoS和DoS T一起调节对缺氧的反应。然而，缺乏功能性DosR的Mtb定殖于C57 B1/6小鼠的肺，推测是由于在该模型中缺乏具有足够缺氧的组织化病变。我们使用C3 HeB/FeJ小鼠比较了Delta-dosR、Delta-dosS和Delta-dosT突变体与Mtb的表型，C3 HeB/FeJ小鼠是一种病变发展为缺氧的替代小鼠模型。通过气溶胶感染C3 HeB/FeJ小鼠。通过组织细菌负荷和组织病理学分析感染的进展。还分析了比较整体免疫反应的测量结果。虽然Delta-dosR和Delta-dosT的生长速度与野生型Mtb相似，但Delta-dosS在体内细菌负荷和病理学方面表现出显著缺陷，并伴有消融的促炎反应。Delta-dosS保留了诱导DosR的能力。Delta-dosS突变体也在离体鼠巨噬细胞中减弱，有证据表明促炎标记的表达减少。我们的研究结果表明，DoS，而不是DosR和DosT，所需的结核分枝杆菌在C3 HeB/FeJ小鼠的生存。Delta-dosS的衰减不是由于其不能诱导DosR调节子，也不是缺氧积累的结果。Delta-dosS的体内生长限制可以离体模拟，表明对巨噬细胞氧化爆发的敏感性。结核病灶内的非干酪性中心最终发展为空洞。我们的研究结果提供了更深入的了解宿主肺内的Mtb持久性的分子机制。
Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the Delta-dosR, Delta-dosS, and Delta-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although Delta-dosR and Delta-dosT grew comparably to wild-type Mtb, Delta-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. Delta-dosS retained the ability to induce DosR. The Delta-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice. The attenuation of Delta-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of Delta-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.