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.
Highlights
Iron is an essential nutrient for virtually every organism
In this study we found that in Aspergillus fumigatus iron starvation results in drastic metabolic changes depending on the transcription factor HapX
We have previously demonstrated the role of SreA in repression of iron acquisition in A. fumigatus [22]
Summary
Iron is an essential nutrient for virtually every organism. The ability to exist in two redox states makes this metal an essential cofactor of proteins involved in numerous major cellular processes including respiration, amino acid metabolism and DNA metabolism. Excess iron has the ability to generate toxic reactive species that can damage cellular components [1]. The bioavailability of iron is very limited owing to its oxidation into insoluble ferric hydroxides by atmospheric oxygen. All organisms have developed tightly regulated homeostatic mechanisms in order to balance uptake, storage and consumption of iron. The mammalian immune system utilizes iron-withholding mechanisms to deny invading microorganism’s access to free iron [2,3]. The control over access to iron is one of the central battlefields deciding the fate of an infection. Iron starvation activates iron uptake and virulence determinants in many prokaryotic and eukaryotic pathogens
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