Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Eur J Immunol. 2011 Feb;41(2):450-60. doi: 10.1002/eji.201040719. Epub 2010 Dec 29.
Mycolic acids (MAs) occur in the cell wall of Mycobacterium tuberculosis as variable mixtures of different classes and chain lengths. Here, we address the relationship between the structure and its inflammatory function of this virulence factor using single synthetic MA isomers, differing in oxygenation class and cis- versus α-methyl-trans proximal cyclopropane orientation. Analysis of bronchoalveolar inflammation, lung histopathology and alveolar macrophage transcription revealed a strong dependence on these meromycolic chemistries of mouse pulmonary inflammation in response to intratracheal treatments with MAs. Whereas α-MA was inert, oxygenated methoxy- and keto-MA with cis-cyclopropane stereochemistry elicited solid to mild inflammatory responses respectively. In trans-cyclopropane orientation, methoxy-MA partially lost its inflammatory activity and keto-MA exerted anti-inflammatory alternative activation of alveolar macrophages and counteracted cis-methoxy-MA induced airway inflammation. The differential innate immune activities of MAs demonstrated here, dependent on oxygenation class and cis versus α-methyl-trans cyclopropane chemistry, identify a novel means for M. tuberculosis to steer host immune responses during infection.
分枝菌酸（MAs）以不同类别和链长的混合物形式存在于结核分枝杆菌的细胞壁中。在这里，我们使用在氧合类别以及顺式与α-甲基-反式近端环丙烷取向方面存在差异的单一合成 MA 异构体来研究这种毒力因子的结构与其炎症功能之间的关系。对支气管肺泡炎症、肺组织病理学和肺泡巨噬细胞转录的分析表明，在对 MA 进行气管内治疗后，这些单甲酯的化学性质强烈依赖于小鼠肺部炎症。α-MA 无活性，而具有顺式环丙烷立体化学的含氧甲氧基和酮基-MA 分别引发了实质性到轻度炎症反应。在反式环丙烷取向中，甲氧基-MA 部分失去了其炎症活性，而酮基-MA 对肺泡巨噬细胞发挥了抗炎替代激活作用，并抵消了顺式甲氧基-MA 诱导的气道炎症。这里展示的 MA 的差异先天免疫活性取决于氧合类别以及顺式与α-甲基-反式环丙烷化学，这为结核分枝杆菌在感染过程中引导宿主免疫反应提供了一种新方法。
