Department of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Innsbruck, Austria.
Mol Immunol. 2011 Sep;48(15-16):2122-9. doi: 10.1016/j.molimm.2011.07.005. Epub 2011 Jul 30.
The mycotoxin gliotoxin is an important metabolite produced by Aspergillus fumigatus, but its precise role in the pathogenesis of cerebral aspergillosis is not yet determined. We could demonstrate that growth in cerebrospinal fluid (CSF) induced the production and secretion of significant amounts of gliotoxin by A. fumigatus. These concentrations of 590-720nM were sufficient to reduce the viability of astrocytes and neurons, as well as of primary microglia, already after few hours of incubation. Annexin staining and electron microscopy revealed the induction of apoptosis rather than necrosis as the relevant mode of gliotoxin action in the brain. Furthermore, even a low gliotoxin concentration of 100nM, which was subtoxic for astrocytes, was able to significantly down-modulate the phagocytic capacity of astrocytes. In order to improve the current antimycotic therapy of cerebral aspergillosis by supporting innate immunity in the fight against Aspergillus, we aimed to neutralize the toxic potency of gliotoxin towards different brain cell types. Compounds such as dithiothreitol (DTT) or glutathione that reduce the internal disulfide bond of gliotoxin were shown here to be able to interfere with the gliotoxin-induced decrease of cell viability and to save the cells from induction of apoptosis. Thus, exploration of these substances may lead to novel approaches for adjunctive treatment of cerebral aspergillosis.
真菌毒素曲霉菌毒素是烟曲霉产生的一种重要代谢产物，但它在脑曲霉病发病机制中的确切作用尚不清楚。我们可以证明，在脑脊液（CSF）中的生长诱导烟曲霉产生和分泌大量的曲霉菌毒素。这些浓度为 590-720nM 的曲霉菌毒素足以在孵育数小时后降低星形胶质细胞和神经元以及原代小胶质细胞的活力。 Annexin 染色和电子显微镜显示，诱导细胞凋亡而不是坏死是曲霉菌毒素在大脑中的相关作用模式。此外，即使是对星形胶质细胞亚毒性的 100nM 低浓度曲霉菌毒素，也能够显著下调星形胶质细胞的吞噬能力。为了通过支持先天免疫来改善目前针对脑曲霉病的抗真菌治疗，我们旨在中和曲霉菌毒素对不同脑细胞类型的毒性。本文表明，能够还原曲霉菌毒素内部二硫键的化合物，如二硫苏糖醇（DTT）或谷胱甘肽，能够干扰曲霉菌毒素诱导的细胞活力下降，并使细胞免于诱导细胞凋亡。因此，对这些物质的探索可能会为脑曲霉病的辅助治疗提供新的方法。
