Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis.
Reductive Power Generated by Mycobacterium leprae Through Cholesterol Oxidation Contributes to Lipid and ATP Synthesis.
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DOI：
10.3389/fcimb.2021.709972
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发表时间：
2021
影响因子：
5.7
通讯作者：
Berrêdo-Pinho M
中科院分区：
文献类型：
--
作者：
Rosa TLSA;Marques MAM;DeBoard Z;Hutchins K;Silva CAA;Montague CR;Yuan T;Amaral JJ;Atella GC;Rosa PS;Mattos KA;VanderVen BC;Lahiri R;Sampson NS;Brennan PJ;Belisle JT;Pessolani MCV;Berrêdo-Pinho M
感染后，麻风分枝杆菌，一种专性细胞内芽孢杆菌，诱导雪旺细胞（SCs）中富含胆固醇的脂滴（ld）的积累。LD被迅速招募到含麻风分枝杆菌的吞噬体中，抑制这一过程会降低细菌的存活率，这表明LD的招募构成了宿主来源的脂质被递送到细胞内麻风分枝杆菌的机制。我们之前证明麻风分枝杆菌只保留了将胆固醇氧化为胆甾酮的能力，这是正常胆固醇分解代谢途径的第一步。在这项研究中，我们研究了胆固醇氧化与sc细菌发病机制的生化相关性。首先，我们发现麻风分枝杆菌增加了受感染SCs对ldl -胆固醇的摄取。此外，荧光显微镜分析显示麻风分枝杆菌与宿主细胞内内化ldl -胆固醇密切相关。利用耻垢分枝杆菌突变株与麻风分枝杆菌基因的互补，我们发现编码3β-羟基类固醇脱氢酶（3β-HSD）的是ml1942，而不是最初注释为胆固醇氧化酶（ChoD）的ml0389。3β-HSD活性产生电子供体NADH和NADPH，分别为麻风分枝杆菌呼吸链提供燃料，并为优势细菌细胞壁脂质硫代酚二真菌酸酯（PDIM）和酚类糖脂(PGL)- 1的生物合成提供还原力。17β-[N-（2,5-二-丁基苯基）氨基甲酰基]-6-氮杂androst-4-烯-3one（化合物1）抑制麻风分枝杆菌3β-HSD活性，可降低SCs中细菌的细胞内存活率。总之，我们的研究结果证实了胆固醇在受感染的SCs中的积累及其潜在的向细胞内细菌的传递。此外，我们提供了强有力的证据，证明胆固醇氧化是麻风分枝杆菌致病性的重要分解代谢途径，并指出3β-HSD是一个主要的药物靶点，可以与目前的多药方案联合使用，缩短麻风治疗时间，改善神经损伤。
Upon infection, Mycobacterium leprae, an obligate intracellular bacillus, induces accumulation of cholesterol-enriched lipid droplets (LDs) in Schwann cells (SCs). LDs are promptly recruited to M. leprae-containing phagosomes, and inhibition of this process decreases bacterial survival, suggesting that LD recruitment constitutes a mechanism by which host-derived lipids are delivered to intracellular M. leprae. We previously demonstrated that M. leprae has preserved only the capacity to oxidize cholesterol to cholestenone, the first step of the normal cholesterol catabolic pathway. In this study we investigated the biochemical relevance of cholesterol oxidation on bacterial pathogenesis in SCs. Firstly, we showed that M. leprae increases the uptake of LDL-cholesterol by infected SCs. Moreover, fluorescence microscopy analysis revealed a close association between M. leprae and the internalized LDL-cholesterol within the host cell. By using Mycobacterium smegmatis mutant strains complemented with M. leprae genes, we demonstrated that ml1942 coding for 3β-hydroxysteroid dehydrogenase (3β-HSD), but not ml0389 originally annotated as cholesterol oxidase (ChoD), was responsible for the cholesterol oxidation activity detected in M. leprae. The 3β-HSD activity generates the electron donors NADH and NADPH that, respectively, fuel the M. leprae respiratory chain and provide reductive power for the biosynthesis of the dominant bacterial cell wall lipids phthiocerol dimycocerosate (PDIM) and phenolic glycolipid (PGL)-I. Inhibition of M. leprae 3β-HSD activity with the 17β-[N-(2,5-di-t-butylphenyl)carbamoyl]-6-azaandrost-4-en-3one (compound 1), decreased bacterial intracellular survival in SCs. In conclusion, our findings confirm the accumulation of cholesterol in infected SCs and its potential delivery to the intracellular bacterium. Furthermore, we provide strong evidence that cholesterol oxidation is an essential catabolic pathway for M. leprae pathogenicity and point to 3β-HSD as a prime drug target that may be used in combination with current multidrug regimens to shorten leprosy treatment and ameliorate nerve damage.
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影响因子：
3.2
作者：
Marques, Maria Angela M.;Berredo-Pinho, Marcia;Pessolani, Maria Cristina V.
通讯作者：
Pessolani, Maria Cristina V.
影响因子：
3.7
作者：
Klink M;Brzezinska M;Szulc I;Brzostek A;Kielbik M;Sulowska Z;Dziadek J
通讯作者：
Dziadek J
影响因子：
2.1
作者：
Brzostek, Anna;Dziadek, Bozena;Dziadek, Jaroslaw
通讯作者：
Dziadek, Jaroslaw
影响因子：
9.4
作者：
FRANZBLAU, SG
通讯作者：
FRANZBLAU, SG
影响因子：
4.8
作者：
Kruh, Nicole A.;Borgaro, Janine G.;Tonge, Peter J.
通讯作者：
Tonge, Peter J.