Induced Synthesis of Mycolactone Restores the Pathogenesis of Mycobacterium ulcerans In Vitro and In Vivo.
Induced Synthesis of Mycolactone Restores the Pathogenesis of Mycobacterium ulcerans In Vitro and In Vivo.
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DOI：
10.3389/fimmu.2022.750643
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发表时间：
2022
影响因子：
7.3
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Strong E;Hart B;Wang J;Orozco MG;Lee S
溃疡分枝杆菌是布鲁里溃疡（BU）的病原体，布鲁里溃疡是第三大常见的分枝杆菌感染。毒性结核分枝溃疡杆菌分泌真菌内酯，一种聚酮毒素。M的大部分观察结果。溃疡感染被描述为坏死性溃疡形式的细胞外环境。虽然有证据表明M.尽管在感染期间存在溃疡，但对分枝杆菌内酯在此过程中发挥的确切作用知之甚少。许多先前的研究依赖于将纯化的分枝菌内酯加入细胞培养系统中来研究其在M.溃疡发病机制和宿主反应调节。然而，这种无菌系统大大简化了M。溃疡分枝杆菌感染模型，并假设菌内酯是唯一相关的毒力因子表达的M。溃疡。在这里，我们表明在M.溃疡性结肠炎感染克服了雷帕霉素（mTOR）信号传导途径的机械靶标的细菌活化，所述mTOR信号传导途径在调节不同的细胞过程（包括自噬和凋亡）中起实质性作用。为进一步研究分枝杆菌内酯在M.溃疡感染，我们已经开发了一个诱导型菌内酯表达系统。利用菌内酯缺陷型穆尔：：Tn 118菌株，该菌株在推定的β-酮酰基转移酶（mup 045）中含有转座子插入，我们通过在四环素诱导型载体系统中表达mup 045成功恢复了菌内酯生产，该系统克服了与组成型互补相关的体外生长缺陷。可诱导的表达分枝杆菌内酯的细菌导致在BU的小鼠足垫模型中建立感染，类似于在用野生型分枝杆菌感染期间观察到的感染。溃疡。该菌内酯诱导系统的建立为进一步研究菌内酯在M.溃疡感染。
Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), the third most common mycobacterial infection. Virulent M. ulcerans secretes mycolactone, a polyketide toxin. Most observations of M. ulcerans infection are described as an extracellular milieu in the form of a necrotic ulcer. While some evidence exists of an intracellular life cycle for M. ulcerans during infection, the exact role that mycolactone plays in this process is poorly understood. Many previous studies have relied upon the addition of purified mycolactone to cell-culture systems to study its role in M. ulcerans pathogenesis and host-response modulation. However, this sterile system drastically simplifies the M. ulcerans infection model and assumes that mycolactone is the only relevant virulence factor expressed by M. ulcerans. Here we show that the addition of purified mycolactone to macrophages during M. ulcerans infection overcomes the bacterial activation of the mechanistic target of rapamycin (mTOR) signaling pathway that plays a substantial role in regulating different cellular processes, including autophagy and apoptosis. To further study the role of mycolactone during M. ulcerans infection, we have developed an inducible mycolactone expression system. Utilizing the mycolactone-deficient Mul::Tn118 strain that contains a transposon insertion in the putative beta-ketoacyl transferase (mup045), we have successfully restored mycolactone production by expressing mup045 in a tetracycline-inducible vector system, which overcomes in-vitro growth defects associated with constitutive complementation. The inducible mycolactone-expressing bacteria resulted in the establishment of infection in a murine footpad model of BU similar to that observed during the infection with wild-type M. ulcerans. This mycolactone inducible system will allow for further analysis of the roles and functions of mycolactone during M. ulcerans infection.
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DOI：
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