Biosynthesis and function of gliotoxin in Aspergillus fumigatus

Scharf, Daniel H.; Heinekamp, Thorsten; Remme, Nicole; Hortschansky, Peter; Brakhage, Axel A.; Hertweck, Christian

doi:10.1007/s00253-011-3689-1

Cited by 177 publications

(164 citation statements)

References 39 publications

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“…A. fumigatus MtfA was found to localize mainly in nuclei, similar to the case in A. nidulans (40), where mtfA was also shown to control the expression of biosynthetic genes involved in the production of secondary metabolites, some with beneficial properties, such as penicillin, and others detrimental, such as the mycotoxin sterigmatocystin (40). For this reason, we evaluated whether A. fumigatus mtfA influences the production of gliotoxin, a compound known for its negative impact on the immune system, including inhibition of phagocytosis and killing of neutrophils (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), as well as acting as an antioxidant (66), facilitating A. fumigatus infection in the lung (67). Overexpression of A. fumigatus mtfA resulted in an increase in gliotoxin production with respect to the control strains.…”

Section: Discussionmentioning

confidence: 99%

The mtfA Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

Smith

Calvo

2014

Eukaryot Cell

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Aspergillus fumigatus is the leading causative agent of invasive aspergillosis (IA). The number of cases is on the rise, with mortality rates as high as 90% among immunocompromised patients. Molecular genetic studies in A. fumigatus could provide novel targets to potentially set the basis for antifungal therapies. In the current study, we investigated the role of the transcription factor gene mtfA in A. fumigatus. Our results revealed that mtfA plays a role in the growth and development of the fungus. Deletion or overexpression of mtfA leads to a slight reduction in colony growth, as well as a reduction in conidiation levels, in the overexpression strain compared to the wild-type strain. Furthermore, production of the secondary metabolite gliotoxin increased when mtfA was overexpressed, coinciding with an increase in the transcription levels of the gliotoxin genes gliZ and gliP with respect to the wild type. In addition, our study showed that mtfA is also necessary for normal protease activity in A. fumigatus; deletion of mtfA resulted in a reduction of protease activity compared to wild-type levels. Importantly, the absence of mtfA caused a decrease in virulence in the Galleria mellonella infection model, indicating that mtfA is necessary for A. fumigatus wild-type pathogenesis.

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Section: Discussionmentioning

confidence: 99%

The mtfA Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

Smith

Calvo

2014

Eukaryot Cell

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“…This cyclization is catalyzed by nonribosomal peptide synthetases and initially leads to the formation of a diketopiperazine. In A. fumigatus, gliotoxin is produced from serine and phenylalanine and contains such a diketopiperazine core structure that is further modified to contain a functionally essential disulfide bridge (31). A diketopiperazine heterocycle can be partially reduced, as it occurs in aspergillic acid.…”

Section: Figmentioning

confidence: 99%

The Volatome of Aspergillus fumigatus

2014

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bEarly detection of invasive aspergillosis is absolutely required for efficient therapy of this fungal infection. The identification of fungal volatiles in patient breath can be an alternative for the detection of Aspergillus fumigatus that still remains problematic. In this work, we investigated the production of volatile organic compounds (VOCs) by A. fumigatus in vitro, and we show that volatile production depends on the nutritional environment. A. fumigatus produces a multiplicity of VOCs, predominantly terpenes and related compounds. The production of sesquiterpenoid compounds was found to be strongly induced by increased iron concentrations and certain drugs, i.e., pravastatin. Terpenes that were always detectable in large amounts were ␣-pinene, camphene, and limonene, as well as sesquiterpenes, identified as ␣-bergamotene and ␤-trans-bergamotene. Other substance classes that were found to be present in the volatome, such as 1-octen-3-ol, 3-octanone, and pyrazines, were found only under specific growth conditions. Drugs that interfere with the terpene biosynthesis pathway influenced the composition of the fungal volatome, and most notably, a block of sesquiterpene biosynthesis by the bisphosphonate alendronate fundamentally changed the VOC composition. Using deletion mutants, we also show that a terpene cyclase and a putative kaurene synthase are essential for the synthesis of volatile terpenes by A. fumigatus. The present analysis of in vitro volatile production by A. fumigatus suggests that VOCs may be used in the diagnosis of infections caused by this fungus.A spergillus fumigatus is an opportunistic fungal pathogen that causes life-threatening invasive pulmonary infections (invasive aspergillosis [IA]) among immunocompromised patients. A sensitive, rapid, and accurate diagnostic assay for invasive aspergillosis is required to successfully fight this fungal infection (1). It has recently been proposed that the detection of volatiles can be used for the diagnosis of pulmonary infections (2, 3) and lung cancer (4, 5). Several aspergilli, including A. flavus, A. ustus, and A. versicolor, have been identified within the scope of environmental studies, where room air was analyzed to detect fungal pollution in houses (6-8). 2-Pentylfuran (2-PF) was detected in the breath of patients with A. fumigatus infection (9). It was shown that A. fumigatus produces farnesene when grown in vitro (10), and the use of terpene volatiles for the detection of IA has recently been proposed (11). However, the spectrum of volatile organic compounds (VOCs) produced by A. fumigatus and their synthesis have been poorly described. In this work, we characterized the patterns of volatile terpenes produced in vitro by A. fumigatus during growth under saprophytic conditions. In addition, the molecular pathways responsible for the synthesis of terpenoid volatiles were defined. MATERIALS AND METHODS Strains.Aspergillus fumigatus strain FGSC A1163 (ϭ DAL ϭ CBS144.89) was used for wild type strain-based experiments. Gene deletions were obta...

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“…3,16 This does not exclude a relevant role of gliotoxin in human invasive infections. Gliotoxin-dependent apoptosis induction may well affect severity and course of Aspergillus infection, for instance by destroying lung epithelium or by killing alveolar macrophages.…”

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confidence: 99%

“…Although the evidence that gliotoxin is an important virulence factor is equivocal, 16 such apoptosis induction may well be relevant to human invasive aspergillosis. It is unlikely that apoptosis induction, or any other effect on human cells, is the benefit that Aspergillus derives from gliotoxin production.…”

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confidence: 99%

A Bim-activating mould

Häcker

2013

Cell Death Differ

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Biosynthesis and function of gliotoxin in Aspergillus fumigatus

Cited by 177 publications

References 39 publications

The mtfA Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

The mtfA Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

The Volatome of Aspergillus fumigatus

A Bim-activating mould

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