In-Vivo Gene Signatures of Mycobacterium tuberculosis in C3HeB/FeJ Mice.
In-Vivo Gene Signatures of Mycobacterium tuberculosis in C3HeB/FeJ Mice.
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DOI：
10.1371/journal.pone.0135208
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kaushal D
中科院分区：
文献类型：
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作者：
Gautam US;Mehra S;Kaushal D
尽管在了解结核分枝杆菌 (Mtb) 的发病机制方面取得了相当大的进展，但事实证明，开发新的治疗方法和疫苗仍然很困难。这至少部分是由于使用了不太理想的体内结核分枝杆菌感染模型，这阻碍了在其实际存在的环境中对病原体的生理学进行研究。 C3HeB/FeJ (Kramnik) 小鼠在实验上感染 Mtb 时会出现类似人类的病变，从而为研究体内病原体的生理学提供了一个可靠且高度易于处理的系统。我们将来自 Kramnik 小鼠肉芽肿的 Mtb 和 DosR (DevR) 调节子中的各种突变体的转录组学与体外培养的进行了比较。我们最近表明突变体 ΔdosS 在 C3HeB/FeJ 小鼠中减弱。小鼠气溶胶暴露于突变分枝杆菌导致 Mtb:ΔdosR 功能类别“信息通路”的转录反应显着不同且相对较弱（< = 20 个基因被诱导）； Mtb 中的“脂质代谢”：ΔdosT； Mtb:ΔdosR 和 Mtb:ΔdosT 中的“毒力、解毒、适应”；与野生型 Mtb H37Rv 相比，所有突变株中的“PE/PPE”家族均存在差异，表明无法将 DosR 功能诱导至不同水平可以调节病原体与宿主的相互作用。 C3HeB/FeJ 小鼠生长过程中表达的 Mtb 基因似乎反映了小鼠肺部对营养利用差异的适应。突变体ΔdosS中下调的glnB、Rv0744c、Rv3281、sdhD/B、mce4A、dctA等基因表明它们对细菌生长和宿主细胞碳/能源流动的需求。我们得出的结论是，在克拉姆尼克小鼠体内慢性感染阶段，结核分枝杆菌中表达的基因主要有助于生长、细胞壁过程、脂质代谢和毒力。
Despite considerable progress in understanding the pathogenesis of Mycobacterium tuberculosis (Mtb), development of new therapeutics and vaccines against it has proven difficult. This is at least in part due to the use of less than optimal models of in-vivo Mtb infection, which has precluded a study of the physiology of the pathogen in niches where it actually persists. C3HeB/FeJ (Kramnik) mice develop human-like lesions when experimentally infected with Mtb and thus make available, a faithful and highly tractable system to study the physiology of the pathogen in-vivo. We compared the transcriptomics of Mtb and various mutants in the DosR (DevR) regulon derived from Kramnik mouse granulomas to those cultured in-vitro. We recently showed that mutant ΔdosS is attenuated in C3HeB/FeJ mice. Aerosol exposure of mice with the mutant mycobacteria resulted in a substantially different and a relatively weaker transcriptional response (< = 20 genes were induced) for the functional category ‘Information Pathways’ in Mtb:ΔdosR; ‘Lipid Metabolism’ in Mtb:ΔdosT; ‘Virulence, Detoxification, Adaptation’ in both Mtb:ΔdosR and Mtb:ΔdosT; and ‘PE/PPE’ family in all mutant strains compare to wild-type Mtb H37Rv, suggesting that the inability to induce DosR functions to different levels can modulate the interaction of the pathogen with the host. The Mtb genes expressed during growth in C3HeB/FeJ mice appear to reflect adaptation to differential nutrient utilization for survival in mouse lungs. The genes such as glnB, Rv0744c, Rv3281, sdhD/B, mce4A, dctA etc. downregulated in mutant ΔdosS indicate their requirement for bacterial growth and flow of carbon/energy source from host cells. We conclude that genes expressed in Mtb during in-vivo chronic phase of infection in Kramnik mice mainly contribute to growth, cell wall processes, lipid metabolism, and virulence.