Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling
Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling
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DOI：
10.1073/pnas.0610634104
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发表时间：
2007-03-20
影响因子：
11.1
通讯作者：
Cox, Jeffery S.
中科院分区：
文献类型：
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作者：
Jain, Madhulika;Petzold, Christopher J.;Cox, Jeffery S.
结核分枝杆菌合成特异性聚酮脂质，其与宿主相互作用并且是毒力所需的。使用质谱方法同时监测数百种脂质，我们发现两种脂质毒力因子，phthiocerol climycerosate（PDIM）和sulfolipid-1（SL-11）的大小和丰度由共同前体甲基丙二酰辅酶A（MMCoA）的可用性控制。与此观点一致，MMCoA水平的增加导致PDIM和SL-1的丰度和质量增加。此外，MMCoA代谢的扰动减弱了小鼠中的病原体复制。重要的是，我们检测到在宿主组织内生长的细菌和在奇数链脂肪酸培养物中生长的细菌中PDIM合成增加。因为M.结核分枝杆菌在感染过程中分解代谢宿主脂质以生长，我们认为M.结核病对体内脂肪酸的影响导致MMCoA通过脂质生物合成途径的通量增加，从而导致毒性脂质合成增加。我们的研究结果表明，在感染过程中转移到宿主脂质代谢允许增加的毒力脂质代谢的细菌。
Mycobacterium tuberculosis synthesizes specific polyketide lipids that interact with the host and are required for virulence. Using a mass spectrometric approach to simultaneously monitor hundreds of lipids, we discovered that the size and abundance of two lipid virulence factors, phthiocerol climycocerosate (PDIM) and sulfolipid-1 (SL-11), are controlled by the availability of a common precursor, methyl malonyl CoA (MMCoA). Consistent with this view, increased levels of MMCoA led to increased abundance and mass of both PDIM and SL-1. Furthermore, perturbation of MMCoA metabolism attenuated pathogen replication in mice. Importantly, we detected increased PDIM synthesis in bacteria growing within host tissues and in bacteria grown in culture on odd-chain fatty acids. Because M. tuberculosis catabolizes host lipids to grow during infection, we propose that growth of M. tuberculosis on fatty acids in vivo leads to increased flux of MMCoA through lipid biosynthetic pathways, resulting in increased virulence lipid synthesis. Our results suggest that the shift to host lipid catabolism during infection allows for increased virulence lipid anabolism by the bacterium.