Sulphur Metabolism Affects Aspergillus fumigatus Pathogenesis

Ref ID: 19515

Author:

J Amich1,3, L Schafferer2, A Beilhack3, H Haas2, S Krappmann1,4

Author address:

1Research Center for Infectious Diseases, Julius-Maximilians-University, Wuerzburg, Germany
2Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innsbruck, Austria
3IZKF, Experimental Stem Cell Transplantation, Poliklinik II, Uni

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Sulphur is an essential macro-element for all living organisms, as S-containing metabolites are
involved in a multitude of fundamental cellular processes. Consequently, all pathogens have to
absorb sulphur compounds from the infected tissue to propagate inside the infected host. Despite
of the importance of sulphur assimilation, its relevance in fungal virulence is largely unexplored.
Here, we describe our efforts to investigate sulphur assimilation in Aspergillus fumigatus, aiming
to broaden the knowledge on fungal virulence and to identify novel targets for antifungal therapy.
Methods:
In a pioneering approach, the A. fumigatus transcription factor MetR was targeted in order to
characterise the in vitro phenotype, gene expression patterns, and virulence capacity of the
corresponding deletion strain. After proving the importance of sulphur assimilation and to interrogate
this pathway further, focus was set on three putative sulphur-containing compounds – sulphate,
cysteine and methionine – that may serve as S-source during invasive pulmonary aspergillosis.
Accordingly, selected genes were targeted to construct deletants strains that allow assessing any
relevance of the specific S-containing compound for intrapulmonary growth of the fungal pathogen.
Results:
We demonstrate that the MetR transcription factor is essential for growth on a variety of sulphur
sources and fundamental for assimilation of inorganic S-sources, but dispensable for utilization of
methionine as it supports expression of genes related to inorganic sulphur assimilation. MetR action
is further required for proper regulation of iron homeostasis, which demonstrates an unprecedented
regulatory crosstalk of sulphur metabolism with this A. fumigatus virulence determinant. Moreover,
MetR is essential for progression of invasive aspergillosis (IA) in leukopenic mice, showing the
importance of sulphur assimilation for virulence. Elimination of the sulphate transporter-encoding
gene sB completely prevents growth on sulphate as sole S-source but does not affect fungal
virulence, demonstrating that uptake of sulphate appears to be dispensable in vivo. A double cysB916;;
mecA916; mutant, which represents a cysteine auxotroph, displays a significant reduction in virulence,
suggesting that cysteine availability is limited in the murine lung. Surprisingly, the methionine
synthase-encoding gene metH916; is essential, proven via heterokaryon rescue and conditional
promoter replacement by a doxycycline-dependent TetOn module. The latter approach furthermore
permitted verification of this gene’s in vivo requirement.
Conclusions:
In this study we demonstrate the importance of sulphur assimilation and particularly of sulphurcontaining
amino acids for A. fumigatus virulence, thereby broadening our understanding of this
fungus’ pathobiology and providing novel targets for antifungal therapy.

Abstract Number: 43

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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