Host-pathogen interactions in tuberculosis laboratory.
Tuberculosis laboratory, and.
JCI Insight. 2020 May 21;5(10):136937. doi: 10.1172/jci.insight.136937.
The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. Here, we show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLECs) in vitro and in the lymph nodes of patients with tuberculosis. We identified via RNA-Seq a transcriptional program that activated, in infected-hLECs, cell survival and cytosolic surveillance of pathogens pathways. Consistent with this, cytosolic access was required for intracellular M. tuberculosis cording. Mycobacteria lacking ESX-1 type VII secretion system or phthiocerol dimycocerosates expression, which failed to access the cytosol, were indeed unable to form cords within hLECs. Finally, we show that M. tuberculosis cording is a size-dependent mechanism used by the pathogen to avoid its recognition by cytosolic sensors and evade either resting or IFN-γ-induced hLEC immunity. These results explain the long-standing association between M. tuberculosis cording and virulence and how virulent mycobacteria use intracellular cording as strategy to successfully adapt and persist in the lymphatic tracts.
结核分枝杆菌形成蛇形索状结构的能力与其毒力密切相关，但结核分枝杆菌索状结构如何促进发病机制尚不清楚。在这里，我们表明，一些结核分枝杆菌临床分离株在体外原代人淋巴管内皮细胞（hLEC）和结核患者的淋巴结中形成细胞内索状结构。我们通过 RNA-Seq 鉴定了一个转录程序，该程序在感染的 hLEC 中激活了细胞存活和病原体细胞质监测途径。与此一致的是，细胞质进入是细胞内结核分枝杆菌索状结构形成所必需的。缺乏 ESX-1 型 VII 型分泌系统或 phthiocerol dimycocerosates 表达的分枝杆菌无法进入细胞质，因此确实无法在 hLEC 内形成索状结构。最后，我们表明，结核分枝杆菌的索状结构是一种大小依赖的机制，病原体利用该机制逃避细胞质传感器的识别，从而逃避静止或 IFN-γ 诱导的 hLEC 免疫。这些结果解释了结核分枝杆菌索状结构与毒力之间的长期关联，以及毒力型分枝杆菌如何利用细胞内索状结构作为成功适应和在淋巴管中持续存在的策略。
