What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus?
What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus?
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DOI：
10.1080/13693780802056012
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发表时间：
2009-01-01
期刊：
影响因子：
2.9
通讯作者：
Sugui, Janyce A.
中科院分区：
文献类型：
--
作者：
Kwon-Chung, Kyung J.;Sugui, Janyce A.
粘胶毒素是表多硫二氧哌嗪类毒素中的一员，也是烟曲霉产生的主要和最有效的毒素。自从在烟曲霉基因组中发现了可能的胶质毒素生物合成12基因簇以来，五个不同的实验室试图确定这种毒素在烟曲霉毒力中的作用。在研究胶质毒素的病理生物学重要性的簇中，被打乱的基因包括编码转录因子的Gliz和编码非核糖体多肽合成酶的gliP。这五个实验室中有两个报告了胶质毒素是烟曲霉的一个重要毒力决定因素，而其他三个实验室则表明它不重要。对五个实验室产生的数据进行比较发现，对小鼠使用的免疫抑制方案是造成观察到的差异的关键因素。无论使用哪种小鼠品系或感染途径，环磷酰胺和皮质类固醇的联合免疫抑制(中性粒细胞减少的小鼠)显示神经胶质毒素并不重要。然而，仅用皮质类固醇抑制小鼠的免疫表明，胶质毒素是烟曲霉的一个重要毒力决定因素。这些研究表明，中性粒细胞减少的小鼠模型不足以揭示真菌次级代谢产物在侵袭性肺曲霉菌病中的病理生物学重要性。
Gliotoxin is a member of the epipolythiodioxopiperazine class of toxins and is both the major and the most potent toxin produced by Aspergillus fumigatus. Since the discovery of the putative gliotoxin biosynthetic 12-gene cluster in the genome of A. fumigatus, five different laboratories have attempted to determine the role of this toxin in the virulence of A. fumigatus. The genes in the cluster that have been disrupted to study the pathobiological importance of gliotoxin include gliZ that encodes a transcription factor and gliP that encodes a nonribosomal peptide synthase. Two of the five laboratories have reported gliotoxin to be an important virulence determinant of A. fumigatus, while the other three laboratories have shown it to be unimportant. Comparisons of the data generated among the five laboratories revealed that the immunosuppressive regimen used for mice was the key factor that contributed to the observed disparity. Regardless of either the mouse strains used or the route of infection, immunosuppression with a combination of cyclophosphamide and corticosteroids (neutropenic mice) showed gliotoxin to be unimportant. The mice immunosuppressed with corticosteroids alone, however, revealed that gliotoxin is an important virulence determinant of A. fumigatus. These studies indicate that the neutropenic mice model is inadequate to reveal the pathobiological importance of fungal secondary metabolites in invasive pulmonary aspergillosis.