Rousseau Cécile, Winter Nathalie, Pivert Elisabeth, Bordat Yann, Neyrolles Olivier, Avé Patrick, Huerre Michel, Gicquel Brigitte, Jackson Mary
Unité de Génétique Mycobactérienne, Institut Pasteur, Paris, France.
Cell Microbiol. 2004 Mar;6(3):277-87. doi: 10.1046/j.1462-5822.2004.00368.x.
The growth of Mycobacterium tuberculosis mutants unable to synthesize phthiocerol dimycocerosates (DIMs) was recently shown to be impaired in mouse lungs. However, the precise role of these molecules in the course of infection remained to be determined. Here, we provide evidence that the attenuation of a DIM-deficient strain takes place during the acute phase of infection in both lungs and spleen of mice, and that this attenuation results in part from the increased sensitivity of the mutant to the cidal activity of reactive nitrogen intermediates released by activated macrophages. We also show that the DIM-deficient mutant, the growth and survival of which were not impaired within resting macrophages and dendritic cells, induced these cells to secrete more tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 than the wild-type strain. Although purified DIM molecules by themselves had no effect on the activation of macrophages and dendritic cells in vitro, we found that the proper localization of DIMs in the cell envelope of M. tuberculosis is critical to their biological effects. Thus, our findings suggest that DIM production contributes to the initial growth of M. tuberculosis by protecting it from the nitric oxide-dependent killing of macrophages and modulating the early immune response to infection.
最近研究表明，无法合成结核硬脂酸二霉菌酸酯（DIMs）的结核分枝杆菌突变体在小鼠肺部的生长受到损害。然而，这些分子在感染过程中的具体作用仍有待确定。在此，我们提供证据表明，DIM缺陷菌株在小鼠肺部和脾脏感染的急性期出现减毒，且这种减毒部分是由于突变体对活化巨噬细胞释放的活性氮中间体的杀伤活性敏感性增加所致。我们还表明，DIM缺陷突变体在静止巨噬细胞和树突状细胞内的生长和存活未受损害，但与野生型菌株相比，它能诱导这些细胞分泌更多的肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6。尽管纯化的DIM分子本身对体外巨噬细胞和树突状细胞的激活没有影响，但我们发现DIMs在结核分枝杆菌细胞壁中的正确定位对其生物学效应至关重要。因此，我们的研究结果表明，DIM的产生通过保护结核分枝杆菌免受巨噬细胞依赖一氧化氮的杀伤以及调节对感染的早期免疫反应，有助于其早期生长。
