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HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus.

ABSTRACT: Iron is essential for a wide range of cellular processes. Here we show that the bZIP-type regulator HapX is indispensable for the transcriptional remodeling required for adaption to iron starvation in the opportunistic fungal pathogen Aspergillus fumigatus. HapX represses iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster and heme biosynthesis. In agreement with the impact on mitochondrial metabolism, HapX-deficiency decreases resistance to tetracycline and increases mitochondrial DNA content. Pathways positively affected by HapX include production of the ribotoxin AspF1 and siderophores, which are known virulence determinants. Iron starvation causes a massive remodeling of the amino acid pool and HapX is essential for the coordination of the production of siderophores and their precursor ornithine. Consistent with HapX-function being limited to iron depleted conditions and A. fumigatus facing iron starvation in the host, HapX-deficiency causes significant attenuation of virulence in a murine model of aspergillosis. Taken together, this study demonstrates that HapX-dependent adaption to conditions of iron starvation is crucial for virulence of A. fumigatus.

SUBMITTER: Schrettl M

PROVIDER: S-EPMC2947994 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus.

Schrettl Markus M Beckmann Nicola N Varga John J Heinekamp Thorsten T Jacobsen Ilse D ID Jöchl Christoph C Moussa Tarek A TA Wang Shaohua S Gsaller Fabio F Blatzer Michael M Werner Ernst R ER Niermann William C WC Brakhage Axel A AA Haas Hubertus H

PLoS pathogens 20100930 9

Iron is essential for a wide range of cellular processes. Here we show that the bZIP-type regulator HapX is indispensable for the transcriptional remodeling required for adaption to iron starvation in the opportunistic fungal pathogen Aspergillus fumigatus. HapX represses iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster and heme biosynthesis. In agreement with the impact on mitochondrial metabolism, HapX-deficiency ...[more]

PMID: 20941352

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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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HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus.

Publications

HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus.

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