VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus
VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus
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DOI：
10.1128/ec.00222-12
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发表时间：
2012-12-01
期刊：
影响因子：
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通讯作者：
Calvo, Ana M.
中科院分区：
文献类型：
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作者：
Dhingra, Sourabh;Andes, David;Calvo, Ana M.
烟曲霉菌侵袭性曲霉病是免疫功能低下患者感染相关死亡的主要原因。在这项研究中，我们证明了Vea，一种真菌特有的主要保守的调控基因，对于这种医学相关真菌的正常形态发生是必要的。虽然Vea基因的缺失导致分生孢子减少，但该基因的过度表达进一步减少了分生孢子的产量，这表明Vea在烟曲霉中起着重要的发育调节作用，正常的分生孢子只有在存在野生型Vea的情况下才能维持。此外，我们的研究表明，VEA是产生胶质毒素的正调控因子，胶质毒素是一种已知的烟曲霉毒力因子次生代谢产物。与野生型对照相比，VEA的缺失导致胶质毒素的产生减少。毒素的减少与GliZ和gliP表达的减少相一致，Gliz和gliP的表达是胶质毒素生物合成所必需的。有趣的是，VEA也影响这种生物体中的蛋白酶活性。具体地说，VEA的缺失导致了蛋白酶活性的降低；这是VEA同源基因在控制真菌水解酶活性方面的第一次报告。虽然VEA影响烟曲霉的几个细胞过程，但在中性粒细胞减少的小鼠感染模型中的致病性研究表明，VEA对毒力是必不可少的。
Invasive aspergillosis by Aspergillus fumigatus is a leading cause of infection-related mortality in immunocompromised patients. In this study, we show that veA, a major conserved regulatory gene that is unique to fungi, is necessary for normal morphogenesis in this medically relevant fungus. Although deletion of veA results in a strain with reduced conidiation, overexpression of this gene further reduced conidial production, indicating that veA has a major role as a regulator of development in A. fumigatus and that normal conidiation is only sustained in the presence of wild-type VeA levels. Furthermore, our studies revealed that veA is a positive regulator in the production of gliotoxin, a secondary metabolite known to be a virulent factor in A. fumigatus. Deletion of veA resulted in a reduction of gliotoxin production with respect to that of the wild-type control. This reduction in toxin coincided with a decrease in gliZ and gliP expression, which is necessary for gliotoxin biosynthesis. Interestingly, veA also influences protease activity in this organism. Specifically, deletion of veA resulted in a reduction of protease activity; this is the first report of a veA homolog with a role in controlling fungal hydrolytic activity. Although veA affects several cellular processes in A. fumigatus, pathogenicity studies in a neutropenic mouse infection model indicated that veA is dispensable for virulence.