The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis
The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis
复制标题
DOI：
10.1074/jbc.m400324200
复制
发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Barry, CE
中科院分区：
文献类型：
--
作者：
Domenech, P;Reed, MB;Barry, CE
为了研究MmpL 8介导的脂质转运在硫苷脂生物合成中的作用，我们在结核分枝杆菌中插入失活mmpL 8基因。该菌株的表征表明，成熟硫脂SL-1的合成被中断，并且在细胞内积累了一种称为SL-N的极性更强的硫酸化分子。SL-N的纯化和结构分析将该分子鉴定为2，3-二酰基-α，α ′-D-海藻糖-2 '-硫酸盐家族。这种结构表明SL-1的运输和生物合成是耦合的，并且硫苷脂生物合成的最后一步可能是两个海藻糖6-位与羟基苯二甲酸的胞外酯化。为了评估这种阴离子表面脂质的损失对毒力的影响，我们通过气溶胶用MmpL 8突变体感染小鼠，发现尽管初始复制率和遏制水平相同，但与野生型相比，观察到MmpL 8突变株在死亡时间上的显着衰减。在感染的早期，细胞因子和细胞因子受体的差异表达显示，突变株有效地抑制关键指标的Th 1型免疫反应，这表明硫苷脂在结核病的发病机制中的免疫调节作用。
To study the role of MmpL8-mediated lipid transport in sulfatide biogenesis, we insertionally inactivated the mmpL8 gene in Mycobacterium tuberculosis. Characterization of this strain showed that the synthesis of mature sulfolipid SL-1 was interrupted and that a more polar sulfated molecule, termed SL-N, accumulated within the cell. Purification of SL-N and structural analysis identified this molecule as a family of 2,3-diacyl-alpha,alpha'-D-trehalose-2'-sulfates. This structure suggests that transport and biogenesis of SL-1 are coupled and that the final step in sulfatide biosynthesis may be the extracellular esterification of two trehalose 6-positions with hydroxyphthioceranic acids. To assess the effect of the loss of this anionic surface lipid on virulence, we infected mice via aerosol with the MmpL8 mutant and found that, although initial replication rates and containment levels were identical, compared with the wild type, a significant attenuation of the MmpL8 mutant strain in time-to-death was observed. Early in infection, differential expression of cytokines and cytokine receptors revealed that the mutant strain less efficiently suppresses key indicators of a Th1-type immune response, suggesting an immunomodulatory role for sulfatides in the pathogenesis of tuberculosis.