Genetic dissection of angiogenesis in the tuberculous granuloma

摘要 结核分枝杆菌每年导致约150万人死亡。它已经有很长时间了 已经观察到分枝杆菌肉芽肿可以广泛地血管化，但 这种血管化的功能后果还没有得到充分的研究。使用 斑马鱼分枝杆菌感染模型概述人类重要方面 分枝杆菌肉芽肿，我们发现肉芽肿诱导的血管生成与 随着局部缺氧的产生和典型亲本基因的转录诱导， 血管生成分子织女素。用临床使用的抑制剂阻断这一通路 结果减轻了负担，改善了结果。根据我们的初步数据， 建议在血管内皮生长因子途径和细菌脂类海藻糖二菌酯中发挥作用，我们将 明确致病分枝杆菌的细胞和分子机制 促进分枝杆菌肉芽肿促血管生成环境，以促进其 自身的成长、传播和生存。我们还将探索一个类似的角色 规范的血管生成信号通路--血管生成素/Tie2通路-- 已经确定了一种新的宿主导向药物，我们已经证明它在减少 斑马鱼体内的分枝杆菌负荷。最后，我们将基于我们最近的数据显示 在人肉芽肿标本中诱导这些通路并探讨其功能 人类基因变异在分枝杆菌感染中的作用总体而言，这项提案测试了 这一假设与肿瘤生物学惊人地平行，血管生成的相互作用， 缺氧和血管受损是分枝杆菌致病的原因之一。 最终，这些通路的调控可能会为寄主提供新的策略。 结核病的定向治疗。

Abstract Mycobacterium tuberculosis kills approximately 1.5 million people annually. It has long been observed that mycobacterial granulomas can be extensively vascularized, but the functional consequences of this vascularization have not been fully examined. Using a zebrafish mycobacterial infection model that recapitulates important aspects of human mycobacterial granulomas, we found that granuloma-induced angiogenesis coincides with the generation of local hypoxia and transcriptional induction of the canonical pro- angiogenic molecule Vegfa. Interception of this pathway with clinically used inhibitors resulted in reduced burden and improved outcome. Building on our preliminary data that suggest a role for the VEGF pathway and the bacterial lipid trehalose dimycolate, we will define the cellular and molecular mechanisms by which pathogenic mycobacteria promote the pro-angiogenic environment of mycobacterial granulomas to facilitate their own growth, dissemination and survival. We also will probe the role of a parallel canonical angiogenic signaling pathway – the angiopoietin/Tie2 pathway – for which we have identified a novel host-directed drug that we have shown to be effective in reducing mycobacterial burden in zebrafish. Finally, we will build on our recent data showing induction of these pathways in human granuloma specimens and probe the functional effects of human genetic variants in mycobacterial infection. Overall, this proposal tests the hypothesis that, in a striking parallel to tumor biology, the interplay of angiogenesis, hypoxia and compromised vasculature contributes to mycobacterial pathogenesis. Ultimately, the modulation of these pathways may provide new strategies for host- directed therapies for tuberculosis.