Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells.
Phthiocerol dimycocerosates promote access to the cytosol and intracellular burden of Mycobacterium tuberculosis in lymphatic endothelial cells.
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DOI：
10.1186/s12915-017-0471-6
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发表时间：
2018-01-04
期刊：
影响因子：
5.4
通讯作者：
Gutierrez MG
中科院分区：
文献类型：
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作者：
Lerner TR;Queval CJ;Fearns A;Repnik U;Griffiths G;Gutierrez MG
硫代苯酚二真菌酸酯（PDIM）是在结核分枝杆菌（Mtb）复合体的毒力成员的外表面发现的糖脂，是结核分枝杆菌发病的一个主要因素。骨髓细胞，如巨噬细胞和树突状细胞，是Mtb感染后的主要宿主，先前的研究表明PDIM在这些细胞中支持Mtb的多种作用。然而，结核分枝杆菌可以感染其他类型的细胞。我们之前的研究表明，结核分枝杆菌在人淋巴内皮细胞（hLECs）中有效地复制，并且hLECs细胞质可作为人淋巴内皮细胞的储存库。在这里，我们研究了PDIM在Mtb转位到hLECs细胞质中的作用。对不能产生PDIM的结核分枝杆菌突变体的分析显示，细菌与膜损伤标志物半乳糖凝集素-8 （Gal8）的共定位较少，表明PDIM对吞噬体膜损伤有重要作用。缺乏这种结核分枝杆菌脂质也会导致结核分枝杆菌与胞内细菌巨噬清除（异体噬）标志物（如泛素、p62和NDP52）共定位的比例降低。透射电子显微镜的hLEC成像显示，缺乏PDIM的Mtb突变体在细胞质中定位的频率要低得多，导致细胞内负荷较低。在hLEC中，PDIM是破坏吞噬体膜所必需的，帮助Mtb避免水解吞噬溶酶体环境。PDIM有助于结核分枝杆菌转移到细胞质中，缺乏PDIM的结核分枝杆菌细胞内负荷减少，表明细胞质是结核分枝杆菌在这些细胞中首选的复制生态位。我们假设Mtb中PDIM合成的药理学靶向可以减少Mtb淋巴库的形成。
Phthiocerol dimycocerosates (PDIM), glycolipids found on the outer surface of virulent members of the Mycobacterium tuberculosis (Mtb) complex, are a major contributing factor to the pathogenesis of Mtb. Myelocytic cells, such as macrophages and dendritic cells, are the primary hosts for Mtb after infection and previous studies have shown multiple roles for PDIM in supporting Mtb in these cells. However, Mtb can infect other cell types. We previously showed that Mtb efficiently replicates in human lymphatic endothelial cells (hLECs) and that the hLEC cytosol acts as a reservoir for Mtb in humans. Here, we examined the role of PDIM in Mtb translocation to the cytosol in hLECs. Analysis of a Mtb mutant unable to produce PDIM showed less co-localisation of bacteria with the membrane damage marker Galectin-8 (Gal8), indicating that PDIM strongly contribute to phagosomal membrane damage. Lack of this Mtb lipid also leads to a reduction in the proportion of Mtb co-localising with markers of macroautophagic removal of intracellular bacteria (xenophagy) such as ubiquitin, p62 and NDP52. hLEC imaging with transmission electron microscopy shows that Mtb mutants lacking PDIM are much less frequently localised in the cytosol, leading to a lower intracellular burden. PDIM is needed for the disruption of the phagosome membrane in hLEC, helping Mtb avoid the hydrolytic phagolysosomal milieu. It facilitates the translocation of Mtb into the cytosol, and the decreased intracellular burden of Mtb lacking PDIM indicates that the cytosol is the preferred replicative niche for Mtb in these cells. We hypothesise that pharmacological targeting of PDIM synthesis in Mtb would reduce the formation of a lymphatic reservoir of Mtb in humans.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
选择性自噬：异种。
影响因子：
4.8
作者：
Bauckman, Kyle A.;Owusu-Boaitey, Nana;Mysorekar, Indira U.
通讯作者：
Mysorekar, Indira U.
影响因子：
6.7
作者：
Astarie-Dequeker C;Le Guyader L;Malaga W;Seaphanh FK;Chalut C;Lopez A;Guilhot C
通讯作者：
Guilhot C
影响因子：
3.4
作者：
Houben, Diane;Demangel, Caroline;Peters, Peter J.
通讯作者：
Peters, Peter J.
影响因子：
64.8
作者：
通讯作者：
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