Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence
Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence
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DOI：
10.1172/jci27335
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Glickman, Michael S.
中科院分区：
文献类型：
--
作者：
Rao, Vivek;Gao, Feng;Glickman, Michael S.
最近的研究表明，结核分枝杆菌细胞被膜脂质的精细结构修饰介导了感染期间宿主细胞的免疫激活。脂质结构的一种此类改变是由α真菌酸近端环丙烷合成酶（pcaA）介导的海藻糖二真菌酸盐（TDM）上的真菌酸的顺式环丙烷修饰，这是早期感染期间的一种促炎脂质修饰。在这里，我们研究的致病作用和免疫调节功能的分枝菌酸环丙烷立体化学表征的M。结核环丙烷-分枝菌酸合酶2（cmaA 2）无效突变体（Δ cmaA 2），其缺乏分枝菌酸的捕获环丙烷化。尽管WT和Delta cmaA 2微生物的滴度在小鼠感染期间相同，但Delta cmaA 2细菌是高毒力的，同时诱导比WT M更大的肉芽肿。结核Delta cmaA 2菌株的高毒力依赖于宿主TNF-α和IFN-γ。环丙烷化增强了M.结核病诱导的巨噬细胞炎症反应，这是一种可以用石油醚提取的脂质转移的表型。最后，纯化的TDM缺乏陷阱环丙烷环是5倍更有效地刺激巨噬细胞。这些结果确立了TDM的cmaA 2依赖性陷阱-环丙烷化作为M.结核病引起的炎症和毒性。此外，分枝菌酸上的环丙烷立体化学直接与宿主细胞相互作用，以积极和消极地影响宿主先天免疫激活。
Recent studies have shown that fine structural modifications of Mycobacterium tuberculosis cell envelope lipids mediate host cell immune activation during infection. One such alteration in lipid structure is cis-cyclopropane modification of the mycolic acids on trehalose dimycolate (TDM) mediated by proximal cyclopropane synthase of alpha mycolates (pcaA), a proinflammatory lipid modification during early infection. Here we examine the pathogenetic role and immunomodulatory function of mycolic acid cyclopropane stereochemistry by characterizing an M. tuberculosis cyclopropane-mycolic acid synthase 2 (cmaA2) null mutant (Delta cmaA2) that lacks traps-cyclopropanation of mycolic acids. Although titers of WT and Delta cmaA2 organisms were identical during mouse infection, Delta cmaA2 bacteria were hypervirulent while inducing larger granulomas than WT M. tuberculosis. The hypervirulence of the Delta cmaA2 strain depended on host TNF-alpha and IFN-gamma. Loss of traps-cyclopropanation enhanced M. tuberculosis-induced macrophage inflammatory responses, a phenotype that was transferable with petroleum ether extractable lipids. Finally, purified TDM lacking traps-cyclopropane rings was 5-fold more potent in stimulating macrophages. These results establish cmaA2-dependent traps-cyclopropanation of TDM as a suppressor of M. tuberculosis-induced inflammation and virulence. In addition, cyclopropane stereochemistries on mycolic acids interact directly with host cells to both positively and negatively influence host innate immune activation.