The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production
The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production
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DOI：
10.1128/jb.00625-15
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发表时间：
2015-12-01
影响因子：
3.2
通讯作者：
Pessolani, Maria Cristina V.
中科院分区：
文献类型：
--
作者：
Marques, Maria Angela M.;Berredo-Pinho, Marcia;Pessolani, Maria Cristina V.
麻风分枝杆菌诱导脂滴的形成，脂滴被募集到感染的巨噬细胞和许旺细胞中含有病原体的吞噬体中。胆固醇是M中丰度增加的脂质之一。麻风病感染的细胞，细胞内的生存依赖于胆固醇的积累。本研究探讨了M.麻风病人获取和代谢胆固醇。计算机模拟分析表明，胆固醇氧化为胆甾-4-烯-3-酮（胆甾烯酮）是由3 β-羟基类固醇脱氢酶（3 β-HSD）催化的胆固醇降解的第一步，显然是结核分枝杆菌中唯一被M.麻风病人细菌与放射性标记胆固醇的孵育证实了计算机模拟预测。孵育M后进行放射性呼吸测定和脂质分析。[4-C-14]胆固醇或[26-C-14]胆固醇的麻风显示该病原体不能代谢作为能量和碳源的胆固醇环或胆固醇侧链。然而，正如预期的那样，细菌贪婪地掺入胆固醇，并在体外和体内将其转化为胆甾烯酮。我们的数据表明M.麻风已经丧失了降解和利用胆固醇作为营养源的能力，但保留了负责将胆固醇氧化为胆甾烯酮的酶。因此，胆固醇代谢在M.麻风病与中央碳代谢和能量产生分离。进一步阐明了在M.麻风感染将建立这种脂质支持M的机制。麻风细胞内生存，并将开辟新的途径，新的麻风病therapy.IMPORTANCEOur研究的重点是专性胞内病原体麻风分枝杆菌及其代谢胆固醇的能力。这些数据为那些有兴趣了解分枝杆菌发病机制的人做出了重要贡献，因为它们表明胆固醇在分枝杆菌发病中的重要作用。麻风细胞内存活不依赖于其作为营养源的利用。我们的研究结果加强了胆固醇在维持M。麻风病感染进一步阐明了在M.麻风感染将建立这种脂质支持M的机制。麻风细胞内存活，并将开辟新的麻风病治疗的新途径。
Mycobacterium leprae induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in M. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of M. leprae to acquire and metabolize cholesterol. In silico analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in Mycobacterium tuberculosis preserved by M. leprae. Incubation of bacteria with radiolabeled cholesterol confirmed the in silico predictions. Radiorespirometry and lipid analyses performed after incubating M. leprae with [4-C-14] cholesterol or [26-C-14] cholesterol showed the inability of this pathogen to metabolize the sterol rings or the side chain of cholesterol as a source of energy and carbon. However, the bacteria avidly incorporated cholesterol and, as expected, converted it to cholestenone both in vitro and in vivo. Our data indicate that M. leprae has lost the capacity to degrade and utilize cholesterol as a nutritional source but retains the enzyme responsible for its oxidation to cholestenone. Thus, the essential role of cholesterol metabolism in the intracellular survival of M. leprae is uncoupled from central carbon metabolism and energy production. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies.IMPORTANCEOur study focused on the obligate intracellular pathogen Mycobacterium leprae and its capacity to metabolize cholesterol. The data make an important contribution for those interested in understanding the mechanisms of mycobacterial pathogenesis, since they indicate that the essential role of cholesterol for M. leprae intracellular survival does not rely on its utilization as a nutritional source. Our findings reinforce the complexity of cholesterol's role in sustaining M. leprae infection. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies.