VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus

Abstract

bInvasive 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.

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

“…Herein, A. niger exposed to GT led to an increase abundance in AglB, LacA and AglA, which are under the control of XlnR. In A. fumigatus, deletion of veA was shown to cause a reduction of protease activity [60]. We conclude that it is possible that the changes observed in the production of hydrolytic enzymes, after GT addition, are mediated by alterations to the Velvet complex.…”

Galleria mellonellaas a host model to studyAspergillus terreusvirulence and amphotericin B resistance

“…A well studied example is A. fumigatus gliotoxin which is known to induce apoptosis and prevents NF-kB activation by inhibition of the proteasome and suppression of angiogenesis. [27][28][29][30][31] Additionally, fumagillin is also produced by A. fumigatus during hyphal growth and has been identified as an inhibitor of angiogenesis through a covalent interaction with methionine aminopeptidase-2 and suppresses tumor growth. 32,33 The production of gliotoxin and fumagillin was also proved in infected G. mellonella larvae.…”

“…At 37 C, all larvae infected with 1 £ 10 7 conidia died within 72 h, while survival still reached 70% in those incubated at 30 C and it took 6 days before all larvae died. Infection with 1 £ 10 6 conidia at 37 C resulted in 100% mortality at day 6, while almost 50% survival was monitored at 30 C. Lower inoculum density (1 £ 10 5 ) resulted in 50% mortality at day 6 at 37 C, whereas larvae kept at 30 C survived the infection (less than 10% mortality). Heat-inactivated conidia of T90 were not able to cause mortality and survival was more than 80% after 120 h incubation at either 30 C or 37 C (data not shown).…”

Transcriptome Analysis of Aspergillus flavus Reveals veA -Dependent Regulation of Secondary Metabolite Gene Clusters, Including the Novel Aflavarin Cluster

“…In spite of these new findings, only a few metabolites have been associated with these clusters (16), among them the clusters associated with the synthesis of kojic acid, as well as the synthesis of AFs, CPA, aflatrem, and asparasone. Expression of these last four gene clusters was shown to be dependent on the global regulatory gene veA, which is also involved in developmental regulation in A. flavus (17)(18)(19)(20) and in other fungi (21)(22)(23)(24)(25)(26). Previous studies, conducted mainly with the model fungus Aspergillus nidulans, revealed that the VeA protein forms a complex with LaeA, a chromatin-modifying protein, and the regulator VelB, another protein of the velvet family.…”