Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute (PHRI) at the University of Medicine and Dentistry of New Jersey (UNDNJ), 225 Warren Street, Newark, New Jersey 07103, USA.
Cell Commun Signal. 2012 Jan 26;10(1):2. doi: 10.1186/1478-811X-10-2.
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.
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.
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.
结核病（TB）是一种由结核分枝杆菌（Mtb）引起的细菌感染，仍然是全球一个重大的健康问题，全球有三分之一的人口感染，每年近 900 万新发病例导致 110 万人死亡。感染 Mtb 后的结果取决于病原体的表型和宿主的免疫状态之间复杂而动态的宿主-病原体相互作用。然而，Mtb 菌株在感染宿主巨噬细胞时诱导不同反应的分子机制尚不完全清楚。为了探索 Mtb 感染巨噬细胞后早期引发的分子事件，我们研究了两种临床 Mtb 菌株（CDC1551 和 HN878）感染小鼠骨髓来源的巨噬细胞（BMM）时的转录反应。这两种菌株先前在小鼠和兔肺结核模型中的毒力/免疫原性方面已显示出差异。
尽管细胞内生长速度相似，但我们观察到与 HN878 相比，CDC1551 感染 BMM 与更高的全局转录组、特定早期（6 小时）免疫反应网络的上调以及一氧化氮产生的显著增加相关。相比之下，与感染 CDC1551 相比，感染 HN878 的 BMM 在 24 小时时，更多参与脂质代谢的宿主基因上调，包括胆固醇代谢和前列腺素合成。与两种 Mtb 菌株感染对巨噬细胞反应的差异相关，细胞内 CDC1551 表达的应激反应基因水平高于 HN878。
与巨噬细胞的早期和更强烈的激活相关，细胞内 CDC1551 细胞暴露于更高水平的应激下，导致细菌应激反应基因的上调增加。相比之下，巨噬细胞的亚最佳激活和诱导宿主细胞脂质代谢失调有利于为 HN878 创造一个压力较小的细胞内环境。我们的研究结果表明，CDC1551 和 HN878 在感染过程中激活巨噬细胞的能力差异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，或者屈服于宿主的保护反应并在兔肺中被驱动进入非复制潜伏状态的能力。
