Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity.
Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity.
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DOI：
10.7554/elife.60648
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发表时间：
2020-11-23
期刊：
影响因子：
7.7
通讯作者：
Bertozzi CR
中科院分区：
文献类型：
--
作者：
Cambier CJ;Banik SM;Buonomo JA;Bertozzi CR
几种毒力脂质存在于致病性分枝杆菌的外细胞壁中。Phthiocerol dimycerosate（PDIM）是一种最丰富的外膜脂质，在抵御宿主抗菌程序和完全逃避这些程序中起着重要作用。感染后，分枝杆菌立即依赖PDIM来逃避Myd 88依赖性的杀微生物单核细胞的募集，这可以清除感染。为了规避使用遗传学来了解毒力脂质的局限性，我们开发了一种化学方法来跟踪斑马鱼感染海分枝杆菌期间的PDIM。我们发现PDIM的甲基分支脂质尾部使其能够扩散到宿主上皮细胞膜中以防止免疫激活。此外，PDIM对胆固醇的亲和力促进了这种表型;用他汀类药物（胆固醇合成抑制剂）治疗斑马鱼，减少了传播并提供了免受感染的保护。这项工作确定了宿主和病原体脂质之间的相互作用影响分枝杆菌的感染性，并建议使用他汀类药物作为结核病预防治疗，抑制PDIM传播。
Several virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection. To circumvent the limitations in using genetics to understand virulence lipids, we developed a chemical approach to track PDIM during Mycobacterium marinum infection of zebrafish. We found that PDIM's methyl-branched lipid tails enabled it to spread into host epithelial membranes to prevent immune activation. Additionally, PDIM’s affinity for cholesterol promoted this phenotype; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread.