Adipocyte Model of Mycobacterium tuberculosis Infection Reveals Differential Availability of Iron to Bacilli in the Lipid-Rich Caseous Environment.
Adipocyte Model of Mycobacterium tuberculosis Infection Reveals Differential Availability of Iron to Bacilli in the Lipid-Rich Caseous Environment.
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DOI：
10.1128/iai.00041-18
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发表时间：
2018-06
影响因子：
3.1
通讯作者：
Gandotra S
中科院分区：
文献类型：
--
作者：
Nandy A;Mondal AK;Pandey R;Arumugam P;Dawa S;Jaisinghani N;Rao V;Dash D;Gandotra S
结核分枝杆菌是一种成功的人类病原体，它利用宿主的多种碳源，但在体内适应富含脂肪酸的环境。我们试图通过使用分化的脂肪细胞作为模型系统来描述结核分枝杆菌对富含脂质环境的生理反应。对感染脂肪细胞和前脂肪细胞的杆菌进行了基于RNA测序的全球转录组分析。在从脂肪细胞分离出来的杆菌中，参与新脂肪酸合成的基因被下调，而那些被预测参与甘油三酯生物合成的基因被上调，表明依赖宿主来源的脂肪酸。转录因子网络分析显示，ider调控基因受到抑制，表明结核分枝杆菌在脂肪细胞模型中铁摄取减少。这种对铁摄取的抑制与脂肪细胞中的铁蛋白和铁水平高于脂肪前细胞相一致。与铁介导氧化应激的作用一致，我们观察到从脂肪细胞分离的结核分枝杆菌中参与减轻氧化应激的基因上调。我们提供的证据表明，油酸（一种主要的宿主来源的脂肪酸）有助于减少细菌的细胞质，从而为对铁介导的氧化应激敏感的结核分枝杆菌突变体提供了一个安全的避风港。通过一种独立的机制，宿主铁蛋白也能够挽救该突变体的生长。我们的工作强调了宿主环境中宏量营养素和微量营养素之间的内在协同作用，它们汇聚在一起，提供对病原体的恢复力。这种由脂肪细胞感染模型提供的复杂协同作用将有助于在干酪样宿主环境中鉴定结核分枝杆菌所需的基因。
Mycobacterium tuberculosis, a successful human pathogen, utilizes multiple carbon sources from the host but adapts to a fatty-acid-rich environment in vivo. We sought to delineate the physiologic response of M. tuberculosis to a lipid-rich environment by using differentiated adipocytes as a model system. Global transcriptome profiling based on RNA sequencing was performed for bacilli from infected adipocytes and preadipocytes. Genes involved in de novo fatty acid synthesis were downregulated, while those predicted to be involved in triglyceride biosynthesis were upregulated, in bacilli isolated from adipocytes, indicating reliance on host-derived fatty acids. Transcription factor network analysis indicated suppression of IdeR-regulated genes, suggesting decreased iron uptake by M. tuberculosis in the adipocyte model. This suppression of iron uptake coincided with higher ferritin and iron levels in adipocytes than in preadipocytes. In accord with the role of iron in mediating oxidative stress, we observed upregulation of genes involved in mitigating oxidative stress in M. tuberculosis isolated from adipocytes. We provide evidence that oleic acid, a major host-derived fatty acid, helps reduce the bacterial cytoplasm, thereby providing a safe haven for an M. tuberculosis mutant that is sensitive to iron-mediated oxidative stress. Via an independent mechanism, host ferritin is also able to rescue the growth of this mutant. Our work highlights the inherent synergy between macronutrients and micronutrients of the host environment that converge to provide resilience to the pathogen. This complex synergy afforded by the adipocyte model of infection will aid in the identification of genes required by M. tuberculosis in a caseous host environment.