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

PLoS Pathog. 2013;9(8):e1003573. doi: 10.1371/journal.ppat.1003573. Epub 2013 Aug 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillus fumigatus / genetics
  • Aspergillus fumigatus / metabolism*
  • Aspergillus fumigatus / pathogenicity*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Female
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Humans
  • Iron / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Pulmonary Aspergillosis / genetics
  • Pulmonary Aspergillosis / metabolism*
  • Pulmonary Aspergillosis / pathology
  • Sulfur / metabolism*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Fungal Proteins
  • Sulfur
  • Iron

Grant support

Funding was received from the German Research Foundation via its Priority Programme SPP1160 (KR2294/1) and the individual research grant KR2294/3-1, the European Science Foundation by the Fuminomics Research Networking Programme (06-RNP-132), the Federal Ministry of Education and Research via the ERA-NET PathoGenoMics co-ordination action (FKZ 0315438B), the Austrian Science Foundation (FWF I282-B09 to HH), as well as from the University of Würzburg, the Free State of Bavaria, the Microbiology Institute at the University Hospital of Erlangen, and the University of Erlangen-Nürnberg (ELAN-12-08-17-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.