Trehalose 6,6′-dimycolate and lipid in the pathogenesis of caseating granulomas of tuberculosis in mice
Trehalose 6,6′-dimycolate and lipid in the pathogenesis of caseating granulomas of tuberculosis in mice
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DOI：
10.2353/ajpath.2006.050848
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发表时间：
2006-04-01
影响因子：
6
通讯作者：
Actor, JK
中科院分区：
文献类型：
--
作者：
Hunter, RL;Olsen, M;Actor, JK
海藻糖6，6 '-二霉菌酸酯（TDM）是从毒性结核分枝杆菌（MTB）表面提取的含量最高、致肉芽肿性最强、毒性最强的脂质。我们进一步研究了它的毒性，这需要通过油性表面活化。将MTB和/或TDM注射到致敏小鼠中诱导以油滴为中心的干酪化肉芽肿。如果在盐水中注射大剂量的MTB，则在脂肪组织中产生干酪化肉芽肿，但是去除表面TDM的MTB仅诱导急性炎症，其不持续。方案的变化产生了几种干酪化肉芽肿的变体，每种变体都具有人类结核病的特征。在每种情况下，MTB在干酪化肉芽肿开始期间定位于脂肪细胞或油滴中，表明坏死是由TDM毒性的毒性激活引起的。将这些发现扩展到肺的证据来自于观察到在致敏小鼠中，与在人类中一样，结核病的发展选择性地刺激脂质在肺泡中的积累。结核分枝杆菌优先与晚期小鼠结核病坏死灶中的脂滴相关。这支持了肺结核将MTB隔离在受保护的环境中的假设，所述受保护的环境累积脂质，直到其能够激活TDM的毒性并引发导致干酪化肉芽肿的坏死。
Trehalose 6,6'-dimycolate (TDM) is the most abundant, most granulomagenic, and most toxic lipid extractable from the surface of virulent Mycobacterium tuberculosis (MTB). We further examined its toxicity, which requires activation by oily surfaces. Injections of MTB and/or TDM into sensitized mice induced caseating granulomas that centered on oil droplets. if large doses of MTB were injected in saline, caseating granulomas developed in adipose tissue, but MTB with surface TDM removed induced only acute inflammation that did not persist. Variations in protocols produced several variants of caseating granulomas, each with characteristics of human tuberculosis. in each instance, MTB were localized in fat cells or oil drops during initiation of caseating granulomas suggesting that necrosis was caused by activation of the toxicity of TDM toxicity. Evidence extending these findings to the lung was derived from the observation that in sensitized mice, as in humans, tuberculosis development stimulates accumulation of lipid selectively in alveoli. MTB preferentially associated with lipid droplets in developing necrotic foci in late-stage murine tuberculosis. This supports the hypothesis that pulmonary tuberculosis sequesters MTB in a protected environment that accumulates lipid until it is able to activate the toxicity of TDM and initiate necrosis that results in caseating granulomas.