Strain specific transcriptional response in Mycobacterium tuberculosis infected macrophages
Strain specific transcriptional response in Mycobacterium tuberculosis infected macrophages
复制标题
DOI：
10.1186/1478-811x-10-2
复制
发表时间：
2012-01-26
影响因子：
8.4
通讯作者：
Kaplan, Gilla
中科院分区：
文献类型：
--
作者：
Koo, Mi-Sun;Subbian, Selvakumar;Kaplan, Gilla
背景：结核病 (TB) 是一种由结核分枝杆菌 (Mtb) 引起的细菌感染，仍然是世界范围内的一个重大健康问题，世界上三分之一的人口受到感染，每年新增病例近 900 万，导致 110 万人死亡。结核分枝杆菌感染后的结果由复杂且动态的宿主-病原体相互作用决定，其中病原体的表型和宿主的免疫状态发挥作用。然而，Mtb菌株在宿主巨噬细胞的细胞内感染过程中诱导不同反应的分子机制尚不完全清楚。为了探索巨噬细胞 Mtb 感染引发的早期分子事件，我们研究了小鼠骨髓源性巨噬细胞 (BMM) 对两种临床 Mtb 菌株 CDC1551 和 HN878 感染的转录反应。先前已证明这些菌株在肺结核小鼠和兔子模型中的毒力/免疫原性不同。 结果：尽管细胞内生长速率相似，但我们观察到，与 HN878 相比，BMM CDC1551 的感染与整体转录组增加、特定早期（6 小时）免疫反应网络上调以及一氧化氮产量显着升高相关。相比之下，与感染CDC1551相比，在HN878感染BMM后24小时，更多参与脂质代谢（包括胆固醇代谢和前列腺素合成）的宿主基因上调。与巨噬细胞对 2 种 Mtb 菌株感染的反应差异相关，细胞内 CDC1551 比 HN878 表达更高水平的应激反应基因。结论：与早期且更强烈的巨噬细胞激活相关，细胞内 CDC1551 细胞暴露于更高水平的应激，导致细菌应激反应基因的上调增加。相比之下，巨噬细胞的次优激活和宿主细胞脂质代谢失调的诱导有利于 HN878 的细胞内环境压力较小。我们的研究结果表明，CDC1551和HN878在感染期间差异性激活巨噬细胞的能力可能决定了它们抵抗宿主细胞免疫并进展为活动性疾病的能力，或者屈服于宿主保护反应并在兔肺中进入非复制潜伏状态的能力。
Background: Tuberculosis (TB), a bacterial infection caused by Mycobacterium tuberculosis (Mtb) remains a significant health problem worldwide with a third of the world population infected and nearly nine million new cases claiming 1.1 million deaths every year. The outcome following infection by Mtb is determined by a complex and dynamic host-pathogen interaction in which the phenotype of the pathogen and the immune status of the host play a role. However, the molecular mechanism by which Mtb strains induce different responses during intracellular infection of the host macrophage is not fully understood. To explore the early molecular events triggered upon Mtb infection of macrophages, we studied the transcriptional responses of murine bone marrow-derived macrophages (BMM) to infection with two clinical Mtb strains, CDC1551 and HN878. These strains have previously been shown to differ in their virulence/immunogenicity in the mouse and rabbit models of pulmonary TB.Results: In spite of similar intracellular growth rates, we observed that compared to HN878, infection by CDC1551 of BMM was associated with an increased global transcriptome, up-regulation of a specific early (6 hours) immune response network and significantly elevated nitric oxide production. In contrast, at 24 hours post-infection of BMM by HN878, more host genes involved in lipid metabolism, including cholesterol metabolism and prostaglandin synthesis were up-regulated, compared to infection with CDC1551. In association with the differences in the macrophage responses to infection with the 2 Mtb strains, intracellular CDC1551 expressed higher levels of stress response genes than did HN878.Conclusions: In association with the early and more robust macrophage activation, intracellular CDC1551 cells were exposed to a higher level of stress leading to increased up-regulation of the bacterial stress response genes. In contrast, sub-optimal activation of macrophages and induction of a dysregulated host cell lipid metabolism favored a less stressful intracellular environment for HN878. Our findings suggest that the ability of CDC1551 and HN878 to differentially activate macrophages during infection probably determines their ability to either resist host cell immunity and progress to active disease or to succumb to the host protective responses and be driven into a non-replicating latent state in rabbit lungs.