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Genome-wide transcriptional changes under oxidative stress in iron-starved Aspergillus fumigatus cultures

ABSTRACT: Aspergillus fumigatus has to cope with a combination of several stress types in the human body, and the interplay between the different stress responses can significantly influence the survival of this human pathogen during the invasion of the host organism. In this study, we examined how the H2O2 induced oxidative stress response depends on iron availability. Surprisingly, the applied H2O2 treatment, which induced only a negligible stress response in iron fed cultures, deleteriously affected the fungus under iron starvation and the majority of observed transcriptome-level stress responses were characteristic only for the combined H2O2-iron starvation stress treatments. Our data suggest that the survival of the fungus highly depended on fragile balances, e.g. between siderophore and ergosterol productions or between economization on iron and production of essential iron containing proteins. The applied stress conditions also affected several processes related to virulence or drug susceptibility including secondary metabolism, zinc acquisition or antifungal drug transport. Our data clearly demonstrate that studying stress responses under single stress treatments is not sufficient at all to understand how fungal pathogens survive in a complex habitat and support the view that the evolutionary success of A. fumigatus as an opportunistic human pathogen is not the mere consequence of the productions of certain virulence factors. Importantly, this fungal pathogen is able to mount and coordinate high-complexity and outstandingly efficient responses to multiple and superpositioning stresses in various harsh habitats like the human body.

ORGANISM(S): Aspergillus fumigatus

PROVIDER: GSE94818 | GEO | 2018/01/01

SECONDARY ACCESSION(S): PRJNA374516

REPOSITORIES: GEO

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Project description:Iron is an essential cofactor for a wide range of cellular processes. Previous studies have shown that siderophore-mediated uptake and intracellular handling of iron are crucial for virulence of Aspergillus fumigatus. Here we show that the bzip-type transcription factor HapX plays a crucial role in the transcriptional remodeling required for adaption to iron starvation in this opportunistic fungal pathogen. HapX was found to be interconnected in a negative feed-back loop with the previously identified iron regulator SreA: SreA repressed expression of hapX during iron sufficiency and HapX repressed sreA during iron starvation. Genome-wide transcriptional profiling and analysis of selected metabolites (protophorphyrine IX, siderophores and amino acids) indicated extensive metabolic remodeling in response to iron starvation. HapX was found to participate in both, repression and activation of genes during iron starvation. HapX was in particular required for repression of iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster biosynthesis and heme biosynthesis. Pathways positively affected by HapX included production of siderophores and the ribotoxin and major allergen AspF1. Analysis of the free amino acid pool revealed HapX-dependent coordination of the production of siderophores with the supply of its precursor ornithine. Consistent with the hapX expression pattern, HapX-deficiency was deleterious with respect to growth rate and conidiation during iron depleted but not iron-replete conditions. HapX-deficiency caused significant attenuation of virulence in a murine model aspergillosis underlining that A. fumigatus faces iron starvation in the host and that the HapX-dependent metabolic reprogramming is therefore crucial for virulence. A. fumigatus 293 and hapX mutants were grown in the presence and absence of iron and in cultures shifted from no iron to iron-containing conditions after 1 h incubation. Hybridizations were performed with biological replicates for wt vs hapX +/- iron. For the iron-shift experiments, there were biological replicates for wt in both conditions and for hapX in -iron but there was only a single biological sample for hapX iron-shift sample. All hybs were performed with flip-dye pairs.

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Genome-wide transcriptional changes under oxidative stress in iron-starved Aspergillus fumigatus cultures

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