Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, LA 70433, USA.
J Infect Dis. 2012 Apr 15;205(8):1203-13. doi: 10.1093/infdis/jis102. Epub 2012 Mar 7.
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 Δ-sigH mutant generates more potent innate immune response than does infection with Mtb. The mutant is attenuated for pathology in mice.
We used a nonhuman primate (NHP) model of acute tuberculosis, to better understand the phenotype of the Δ-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.
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:Δ-sigH mutant did not exhibit acute tuberculosis, instead showing significantly blunted disease. These NHPs survived the entire duration of the study.
The Mtb:Δ-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.
Sigma H（sigH）是结核分枝杆菌（Mtb）的主要应激反应因子。它是在受热、氧化应激、细胞壁损伤和缺氧时诱导产生的。与感染 Mtb 相比，巨噬细胞感染Δ-sigH 突变体可产生更强的先天免疫反应。该突变体在小鼠中的病理表现减弱。
我们使用了一种非人类灵长类动物（NHP）急性结核模型，以便更好地了解体内Δ-sigH 突变体的表型。NHPs 感染高剂量的 Mtb 或突变体，通过临床、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，表现为临床相关指标恶化、肺部细菌负荷高和肉芽肿性免疫病理学。所有动物都迅速死于结核病。另一方面，暴露于 Mtb:Δ-sigH 突变体的 NHP 并未出现急性结核病，而是表现出明显的疾病缓解。这些 NHP 存活了整个研究期间。
Mtb:Δ-sigH 突变体在 NHP 中的细菌负荷和免疫病理学方面完全减弱。SigH 及其调控子是灵长类动物完全毒力所必需的。需要进一步研究以确定这种衰减的分子机制。
