Mycolactone Diffuses from Mycobacterium ulcerans-Infected Tissues and Targets Mononuclear Cells in Peripheral Blood and Lymphoid Organs
Mycolactone Diffuses from Mycobacterium ulcerans-Infected Tissues and Targets Mononuclear Cells in Peripheral Blood and Lymphoid Organs
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DOI：
10.1371/journal.pntd.0000325
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发表时间：
2008-10-01
影响因子：
3.8
通讯作者：
Demangel, Caroline
中科院分区：
文献类型：
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作者：
Hong, Hui;Coutanceau, Emmanuelle;Demangel, Caroline
背景：布鲁里溃疡（BU）是由溃疡分枝杆菌引起的皮下组织进行性疾病。 BU 病变的病理学与具有杀细胞和免疫抑制特性的可扩散物质、分枝菌内酯的局部产生有关。 BU 病变中的缺陷炎症反应反映了毒素的这些生物学特性。然而，分枝菌内酯是否从感染组织中扩散并抑制 BU 患者的 IFN-γ 反应仍不清楚。 方法/主要发现：在这里，我们通过追踪毒素的放射性标记形式，并通过直接定量内脏和细胞亚群脂质提取物中的分枝菌内酯，研究了在动物模型中注射后分枝菌内酯的药物分布。我们发现，皮下递送的分枝菌内酯扩散到小鼠外周血中，并在具有特定脾脏倾向的内脏器官中积累。当小鼠皮下感染溃疡分枝杆菌时，分枝杆菌内酯的分布模式相似。没有证据表明分枝菌内酯在感染期间在血清中循环。然而，在溃疡性病变出现前几周，在血液、淋巴结和脾脏的单核细胞中发现了结构完整的毒素。重要的是，分枝杆菌内酯扩散到溃疡分枝杆菌感染小鼠的血液中与循环淋巴细胞功能的改变同时发生。结论：除了提供分枝杆菌内酯扩散到溃疡分枝杆菌感染部位之外的第一个证据外，我们的结果还支持该毒素在全身水平发挥免疫抑制作用的假设。此外，他们建议基于循环血细胞中分枝菌内酯检测的测定可考虑用于早期疾病的诊断测试。
Background: Buruli ulcer (BU) is a progressive disease of subcutaneous tissues caused by Mycobacterium ulcerans. The pathology of BU lesions is associated with the local production of a diffusible substance, mycolactone, with cytocidal and immunosuppressive properties. The defective inflammatory responses in BU lesions reflect these biological properties of the toxin. However, whether mycolactone diffuses from infected tissues and suppresses IFN-gamma responses in BU patients remains unclear.Methodology/Principal Findings: Here we have investigated the pharmacodistribution of mycolactone following injection in animal models by tracing a radiolabeled form of the toxin, and by directly quantifying mycolactone in lipid extracts from internal organs and cell subpopulations. We show that subcutaneously delivered mycolactone diffused into mouse peripheral blood and accumulated in internal organs with a particular tropism for the spleen. When mice were infected subcutaneously with M. ulcerans, this led to a comparable pattern of distribution of mycolactone. No evidence that mycolactone circulated in blood serum during infection could be demonstrated. However, structurally intact toxin was identified in the mononuclear cells of blood, lymph nodes and spleen several weeks before ulcerative lesions appear. Importantly, diffusion of mycolactone into the blood of M. ulcerans-infected mice coincided with alterations in the functions of circulating lymphocytes.Conclusion: In addition to providing the first evidence that mycolactone diffuses beyond the site of M. ulcerans infection, our results support the hypothesis that the toxin exerts immunosuppressive effects at the systemic level. Furthermore, they suggest that assays based on mycolactone detection in circulating blood cells may be considered for diagnostic tests of early disease.