igr Genes and Mycobacterium tuberculosis Cholesterol Metabolism
igr Genes and Mycobacterium tuberculosis Cholesterol Metabolism
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DOI：
10.1128/jb.00452-09
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发表时间：
2009-08-15
影响因子：
3.2
通讯作者：
Sherman, David R.
中科院分区：
文献类型：
--
作者：
Chang, Jennifer C.;Miner, Maurine D.;Sherman, David R.
最近，胆固醇被确定为慢性结核分枝杆菌感染小鼠存活的重要生理营养物质。然而，目前尚不清楚这种细菌什么时候可以获得胆固醇，以及它的代谢需要哪些额外的细菌功能。在这里，我们证明了igr位点，我们之前发现它对结核分枝杆菌的细胞内生长和毒力至关重要，也是胆固醇代谢所必需的。虽然缺乏igr的菌株在短链和长链脂肪酸存在的情况下与野生型生长相同，但这些细菌的生长在胆固醇存在的情况下完全受到抑制。有趣的是，这种突变体在胆固醇依赖性生长抑制下仍然能够呼吸，这表明在胆固醇中毒期间细菌可以代谢其他碳源。与这一假设一致，我们发现胆固醇在体外的生长抑制作用取决于胆固醇的进口，因为mce4胆固醇摄取系统的突变部分抑制了这种作用。此外，在疾病早期，Delta igr突变体的生长缺陷被mce4突变完全抑制，这表明胆固醇中毒是衰减的主要机制。我们得出结论，结核分枝杆菌在整个感染过程中代谢胆固醇。
Recently, cholesterol was identified as a physiologically important nutrient for Mycobacterium tuberculosis survival in chronically infected mice. However, it remained unclear precisely when cholesterol is available to the bacterium and what additional bacterial functions are required for its metabolism. Here, we show that the igr locus, which we previously found to be essential for intracellular growth and virulence of M. tuberculosis, is required for cholesterol metabolism. While igr-deficient strains grow identically to the wild type in the presence of short- and long-chain fatty acids, the growth of these bacteria is completely inhibited in the presence of cholesterol. Interestingly, this mutant is still able to respire under cholesterol-dependent growth inhibition, suggesting that the bacteria can metabolize other carbon sources during cholesterol toxicity. Consistent with this hypothesis, we found that the growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as mutation of the mce4 sterol uptake system partially suppresses this effect. In addition, the Delta igr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout infection.