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Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

Amich J, Schafferer L, Haas H, Krappmann S - PLoS Pathog. (2013)

Bottom Line: Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent.The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus.Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Infectious Diseases, Julius-Maximilians-University Würzburg, Würzburg, Germany.

ABSTRACT
Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

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Utilization but not production of volatile sulphur compounds by A. fumigatus is independent of MetR.Cross-feeding experiments with the wild-type isolate and its metRΔ derivative were carried out on spatially separated culture media that allow gaseous exchange of volatile compounds. Growth of externally inoculated A. fumigatus demonstrates that this fungus can utilize volatile sulphur compounds (VSCs) that are produced in the course of methionine catabolism by the internally inoculated isolate. Production of VSCs does not require MetR, as demonstrated by growth of the wild-type isolate when the respective mutant strain is grown on methionine-containing medium. In contrast can the metRΔ strain not use VSC as sole source of sulphur.
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ppat-1003573-g004: Utilization but not production of volatile sulphur compounds by A. fumigatus is independent of MetR.Cross-feeding experiments with the wild-type isolate and its metRΔ derivative were carried out on spatially separated culture media that allow gaseous exchange of volatile compounds. Growth of externally inoculated A. fumigatus demonstrates that this fungus can utilize volatile sulphur compounds (VSCs) that are produced in the course of methionine catabolism by the internally inoculated isolate. Production of VSCs does not require MetR, as demonstrated by growth of the wild-type isolate when the respective mutant strain is grown on methionine-containing medium. In contrast can the metRΔ strain not use VSC as sole source of sulphur.

Mentions: Because the AfS167 strain is unable to grow in the presence of S2− (Fig. 2A) and as it is known that several fungi, including Aspergillus species, produce volatile sulphur compounds (VSCs) like hydrogen sulphide (H2S), dimethylsulphide (H3C-S-CH3), or methanethiol (CH3-SH) as a result of methionine catabolism [49], [50], [51], we became interested in studying whether A. fumigatus would be able to utilize such volatile compounds as S-source and if generation of such VSCs is MetR-dependent. The wild-type and metRΔ strains were cultured in small petri dishes with minimal medium containing methionine as sulphur source. These plates were placed inside larger petri dishes with medium lacking any S-source. Neither the wild-type isolate nor the mutant was able to grow in the absence of any sulphur source (not shown). However, when either strain was grown on the methionine-containing petri dish, growth on the outside sulphur-depleted medium was observed only for the wild-type strain (Fig. 4). Accordingly, A. fumigatus is able to take up VSCs produced from methionine catabolism and to use them as S-source. Production of VSCs appears to be independent from the presence of the MetR regulator but their utilization as S-source requires the presence of this regulatory factor.


Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

Amich J, Schafferer L, Haas H, Krappmann S - PLoS Pathog. (2013)

Utilization but not production of volatile sulphur compounds by A. fumigatus is independent of MetR.Cross-feeding experiments with the wild-type isolate and its metRΔ derivative were carried out on spatially separated culture media that allow gaseous exchange of volatile compounds. Growth of externally inoculated A. fumigatus demonstrates that this fungus can utilize volatile sulphur compounds (VSCs) that are produced in the course of methionine catabolism by the internally inoculated isolate. Production of VSCs does not require MetR, as demonstrated by growth of the wild-type isolate when the respective mutant strain is grown on methionine-containing medium. In contrast can the metRΔ strain not use VSC as sole source of sulphur.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757043&req=5

ppat-1003573-g004: Utilization but not production of volatile sulphur compounds by A. fumigatus is independent of MetR.Cross-feeding experiments with the wild-type isolate and its metRΔ derivative were carried out on spatially separated culture media that allow gaseous exchange of volatile compounds. Growth of externally inoculated A. fumigatus demonstrates that this fungus can utilize volatile sulphur compounds (VSCs) that are produced in the course of methionine catabolism by the internally inoculated isolate. Production of VSCs does not require MetR, as demonstrated by growth of the wild-type isolate when the respective mutant strain is grown on methionine-containing medium. In contrast can the metRΔ strain not use VSC as sole source of sulphur.
Mentions: Because the AfS167 strain is unable to grow in the presence of S2− (Fig. 2A) and as it is known that several fungi, including Aspergillus species, produce volatile sulphur compounds (VSCs) like hydrogen sulphide (H2S), dimethylsulphide (H3C-S-CH3), or methanethiol (CH3-SH) as a result of methionine catabolism [49], [50], [51], we became interested in studying whether A. fumigatus would be able to utilize such volatile compounds as S-source and if generation of such VSCs is MetR-dependent. The wild-type and metRΔ strains were cultured in small petri dishes with minimal medium containing methionine as sulphur source. These plates were placed inside larger petri dishes with medium lacking any S-source. Neither the wild-type isolate nor the mutant was able to grow in the absence of any sulphur source (not shown). However, when either strain was grown on the methionine-containing petri dish, growth on the outside sulphur-depleted medium was observed only for the wild-type strain (Fig. 4). Accordingly, A. fumigatus is able to take up VSCs produced from methionine catabolism and to use them as S-source. Production of VSCs appears to be independent from the presence of the MetR regulator but their utilization as S-source requires the presence of this regulatory factor.

Bottom Line: Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent.The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus.Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Infectious Diseases, Julius-Maximilians-University Würzburg, Würzburg, Germany.

ABSTRACT
Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

Show MeSH
Related in: MedlinePlus