Mycolactone is responsible for the painlessness of Mycobacterium ulcerans infection (Buruli ulcer) in a murine study
Mycolactone is responsible for the painlessness of Mycobacterium ulcerans infection (Buruli ulcer) in a murine study
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DOI：
10.1128/iai.01588-07
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发表时间：
2008-05-01
影响因子：
3.1
通讯作者：
Small, Pamela L. C.
中科院分区：
文献类型：
--
作者：
En, Junichiro;Goto, Masamichi;Small, Pamela L. C.
布鲁里溃疡是由溃疡分枝杆菌引起的一种慢性皮肤病，它产生一种有毒的脂质分枝杆菌内酯。尽管有广泛的坏死和组织损伤，病变是无痛的。这种疼痛的消失阻止了患者寻求早期治疗，因此，许多患者经历严重的后遗症，包括截肢。我们曾报道小鼠接种M.溃疡表现为痛觉丧失和神经变性。然而，导致神经损伤的分子尚未确定。为了阐明单独的菌内酯是否可以诱导神经损伤，将菌内酯A/B注射到BALB B/c小鼠的足垫。总共100 μ g的霉菌内酯引起足垫肿胀、发红和糜烂。von Frey感觉测试显示第7天感觉过敏，第21天恢复，第28天感觉减退。在组织学上，足垫显示表皮糜烂、中度基质水肿和中度嗜中性粒细胞浸润，直至第14天，逐渐消退。第7天和第14天，神经束出现神经内出血、嗜中性粒细胞浸润和雪旺细胞核丢失。超微结构上，髓鞘空泡样改变开始于第14天，到第42天逐渐消退，但有髓纤维的密度仍然很低。这项研究表明，最初的感觉过敏，其次是感觉恢复和最终的感觉减退。我们目前的研究表明，真菌内酯直接损害神经，是负责没有疼痛特征的布鲁里溃疡。此外，注射200 μ g菌内酯的小鼠显示肺出血。这是第一项证明真菌内酯全身作用的研究。
Buruli ulcer is a chronic skin disease caused by Mycobacterium ulcerans, which produces a toxic lipid mycolactone. Despite the extensive necrosis and tissue damage, the lesions are painless. This absence of pain prevents patients from seeking early treatment and, as a result, many patients experience severe sequelae, including limb amputation. We have reported that mice inoculated with M. ulcerans show loss of pain sensation and nerve degeneration. However, the molecules responsible for the nerve damage have not been identified. In order to clarify whether mycolactone alone can induce nerve damage, mycolactone A/B was injected to footpads of BALB/c mice. A total of 100 mu g of mycolactone induced footpad swelling, redness, and erosion. The von Frey sensory test showed hyperesthesia on day 7, recovery on day 21, and hypoesthesia on day 28. Histologically, the footpads showed epidermal erosion, moderate stromal edema, and moderate neutrophilic infiltration up to day 14, which gradually resolved. Nerve bundles showed intraneural hemorrhage, neutrophilic infiltration, and loss of Schwann cell nuclei on days 7 and 14. Ultra structurally, vacuolar change of myelin started on day 14 and gradually subsided by day 42, but the density of myelinated fibers remained low. This study demonstrated that initial hyperesthesia is followed by sensory recovery and final hypoesthesia. Our present study suggests that mycolactone directly damages nerves and is responsible for the absence of pain characteristic of Buruli ulcer. Furthermore, mice injected with 200 mu g of mycolactone showed pulmonary hemorrhage. This is the first study to demonstrate the systemic effects of mycolactone.