期刊
BMC BIOLOGY
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12915-017-0471-6
关键词
Mycobacterium tuberculosis; Tuberculosis; Phthiocerol dimycocerosates; PDIM; Lymphatic endothelial cells; hLEC; Macrophages; Phagosome damage; Cytosol; Xenophagy
类别
资金
- Francis Crick Institute - Cancer Research UK [FC001092]
- UK Medical Research Council [FC001092, MC_UP_1202/11]
- Wellcome Trust [FC001092]
- German Research Foundation [DFG SPP1580]
- Medical Research Council [MC_UP_1202/11] Funding Source: researchfish
- The Francis Crick Institute [10092] Funding Source: researchfish
- MRC [MC_UP_1202/11] Funding Source: UKRI
Background: 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. Results: 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. Conclusions: 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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