The Mycobacterium tuberculosis Stress Response Factor SigH Is Required for Bacterial Burden as Well as Immunopathology in Primate Lungs
The Mycobacterium tuberculosis Stress Response Factor SigH Is Required for Bacterial Burden as Well as Immunopathology in Primate Lungs
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DOI：
10.1093/infdis/jis102
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发表时间：
2012-04-15
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：
Mehra, Smriti;Golden, Nadia A.;Kaushal, Deepak
背景Sigma H（sigH）是结核分枝杆菌（Mtb）的主要应激反应因子。它是由热、氧化应激、细胞壁损伤和缺氧引起的。感染巨噬细胞的δ-sigH突变体产生更有力的先天免疫反应比感染结核分枝杆菌。突变体在小鼠中的病理学是减毒的。我们使用非人灵长类动物（NHP）急性结核病模型，以更好地了解体内的delta-sigH突变体的表型。NHP感染高剂量的结核分枝杆菌或突变株，使用临床、病理、微生物学和免疫学参数分析两组结核病的进展情况。暴露于Mtb的动物迅速进展为急性肺结核，如恶化的临床相关性、高肺细菌负荷和肉芽肿性免疫病理学所示。所有的动物都很快死于肺结核。另一方面，暴露于Mtb：delta-sigH突变体的NHP没有表现出急性结核病，而是显示出显著钝化的疾病。这些NHP在整个研究期间存活。Mtb：delta-sigH突变体在NHP中的细菌负荷以及免疫病理学方面完全减毒。SigH及其调节子是灵长类动物中完全毒力所必需的。需要进一步的研究来确定这种衰减的分子机制。
Background. Sigma H (sigH) is a major Mycobacterium tuberculosis (Mtb) stress response factor. It is induced in response to heat, oxidative stress, cell wall damage, and hypoxia. Infection of macrophages with the delta-sigH mutant generates more potent innate immune response than does infection with Mtb. The mutant is attenuated for pathology in mice.Methods. We used a nonhuman primate (NHP) model of acute tuberculosis, to better understand the phenotype of the delta-sigH mutant in vivo. NHPs were infected with high doses of Mtb or the mutant, and the progression of tuberculosis was analyzed in both groups using clinical, pathological, microbiological, and immunological parameters.Results. Animals exposed to Mtb rapidly progressed to acute pulmonary tuberculosis as indicated by worsening clinical correlates, high lung bacterial burden, and granulomatous immunopathology. All the animals rapidly succumbed to tuberculosis. On the other hand, the NHPs exposed to the Mtb:delta-sigH mutant did not exhibit acute tuberculosis, instead showing significantly blunted disease. These NHPs survived the entire duration of the study.Conclusions. The Mtb:delta-sigH mutant is completely attenuated for bacterial burden as well as immunopathology in NHPs. SigH and its regulon are required for complete virulence in primates. Further studies are needed to identify the molecular mechanism of this attenuation.