Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids.
Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids.
复制标题
DOI：
10.1371/journal.ppat.1000289
复制
发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
Guilhot C
中科院分区：
文献类型：
--
作者：
Astarie-Dequeker C;Le Guyader L;Malaga W;Seaphanh FK;Chalut C;Lopez A;Guilhot C
邻苯二甲酸甘油酯(DIM)是结核分枝杆菌(Mtb)的主要毒力因子，特别是在感染的早期阶段，当细菌与宿主巨噬细胞接触时，DIM更是如此。然而，它们的细胞和分子作用机制仍不清楚。利用缺失DIM生物合成相关基因的Mtb突变体，我们证明DIM既参与Mtb的受体依赖的吞噬作用，又参与防止吞噬小体的酸化。DIM的作用需要膜流动性的状态，用降胆固醇药物进行的实验证明了这一点，该实验消除了野生型和突变菌株之间观察到的吞噬效率和吞噬小体酸化的差异。在活细胞中插入新的胆固醇-芘探针表明，膜疏水核心的极性在与Mtb接触时发生了变化，而胆固醇的横向扩散没有受到影响。这种效应依赖于DIM，并且与在模型膜中插入DIM后观察到的效应一致。因此，我们认为DIM通过靶向宿主膜上的脂质组织，从而改变其生物物理性质来控制Mtb对巨噬细胞的侵袭。DIM诱导的脂质有序性改变有利于受体介导的Mtb吞噬效率，并有助于控制吞噬体pH驱动保护生态位中的细菌。结核分枝杆菌(Mtb)是人类结核病的病原体，是一种极为成功的人类病原体。细菌的致病机制与其入侵巨噬细胞和绕过宿主细胞的杀菌功能以在保护生态位内生存的能力有关。细胞机制在很大程度上得到了研究，但细菌因素知之甚少。分枝杆菌细胞被膜的最外层特别令人感兴趣，因为它位于与巨噬细胞的界面上。这个信封的一个有趣的特点是它的高脂肪含量。其中一类脂类，即邻苯二甲酸甘油酯(DIM)，自从被证明可以促进结核分枝杆菌的毒力以来，一直被广泛研究。我们研究了DIM的细胞和分子机制，证明DIM通过识别细菌后质膜重组的机制参与了人巨噬细胞对结核分枝杆菌的受体依赖性吞噬。这种质膜生物物理性质的改变可能有助于结核分枝杆菌通过防止其吞噬小体的酸化来创造一个保护性的生态位。我们的结果为DIM的分子作用机制提供了第一条线索，DIM是一种关键的Mtb脂类毒力因子。
Phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), in particular during the early step of infection when bacilli encounter their host macrophages. However, their cellular and molecular mechanisms of action remain unknown. Using Mtb mutants deleted for genes involved in DIM biosynthesis, we demonstrated that DIM participate both in the receptor-dependent phagocytosis of Mtb and the prevention of phagosomal acidification. The effects of DIM required a state of the membrane fluidity as demonstrated by experiments conducted with cholesterol-depleting drugs that abolished the differences in phagocytosis efficiency and phagosome acidification observed between wild-type and mutant strains. The insertion of a new cholesterol-pyrene probe in living cells demonstrated that the polarity of the membrane hydrophobic core changed upon contact with Mtb whereas the lateral diffusion of cholesterol was unaffected. This effect was dependent on DIM and was consistent with the effect observed following DIM insertion in model membrane. Therefore, we propose that DIM control the invasion of macrophages by Mtb by targeting lipid organisation in the host membrane, thereby modifying its biophysical properties. The DIM-induced changes in lipid ordering favour the efficiency of receptor-mediated phagocytosis of Mtb and contribute to the control of phagosomal pH driving bacilli in a protective niche. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, is an extremely successful human pathogen. The pathogenesis of bacterium is associated with its ability to invade macrophages and to circumvent bactericidal functions of the host cell in order to survive within a protective niche. The cellular mechanisms are largely investigated but the bacterial factors are poorly known. The outermost layer of the mycobacterial cell envelope is particularly of interest because of its localization at the interface with macrophages. An interesting feature of this envelope is its high lipid content. One group of lipids, the phthiocerol dimycocerosates (DIM), has been studied intensively since being shown to promote Mtb virulence. We investigated the cellular and molecular mechanisms of DIM and demonstrated that DIM participate in the receptor-dependent phagocytosis of Mtb in human macrophages through a mechanism involving a reorganization of the plasma membrane following recognition of bacilli. This modification of the plasma membrane biophysical properties might help Mtb to create a protective niche by preventing acidification of its phagosome. Our results provide a first hint on the molecular mechanism of action of DIM, a key Mtb lipidic virulence factor.
登录
查看更多内容
影响因子：
3.4
作者：
de Chastellier, C;Thilo, L
通讯作者：
Thilo, L
影响因子：
4.5
作者：
Beatty, WL;Rhoades, ER;Russell, DG
通讯作者：
Russell, DG
影响因子：
2.8
作者：
Indrigo, J;Hunter, RL;Actor, JK
通讯作者：
Actor, JK
人类巨噬细胞甘露糖受体指导结核分枝杆菌脂肪氨基氨基甘氨酸介导的吞噬体生物发生。
DOI：
10.1084/jem.20051239
发表时间：
2005-10-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kang PB;Azad AK;Torrelles JB;Kaufman TM;Beharka A;Tibesar E;DesJardin LE;Schlesinger LS
通讯作者：
Schlesinger LS
影响因子：
2.8
作者：
Bardarov, S;Bardarov, S;Jacobs, WR
通讯作者：
Jacobs, WR