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.

Iron competition in fungus-plant interactions

“…2,4,5,11 We found that deletion of hapX in F. oxysporum had no effect on mycelial growth on iron-sufficient media, but dramatically reduced growth under iron-depleted conditions. 12 Interestingly, as reported in Candida albicans, 4 the F. oxysporum ΔhapX mutant was fully competent in iron uptake. In agreement with this result, transcription of siderophore genes was strongly induced during iron-depleted conditions both in the wild type strain and the ΔhapX mutant.…”

“…[2][3][4][5] Here we investigated the role of iron homeostasis in the soilborne fungal plant pathogen Fusarium oxysporum. Since soluble Fe 3+ in natural soils represents only ~10 -10 M at equilibrium with soil iron 6 and plant roots have efficient iron-sequestering mechanisms, 7 we hypothesized that iron homeostasis should play an important role during root infection.…”

“…[2][3][4][5] Transcriptional upregulation of genes during iron starvation, including hapX, sidA (siderophore biosynthesis precursor) or srbA (iron acquisition in response to hypoxia), was observed during early stages of plant infection and when F. oxysporum was shifted from minimal medium to human blood. 12 Genomewide transcript profiling revealed a large number of genes whose expression is activated under iron starvation conditions in a HapX-dependent manner.…”

Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus

“…For quantification of extra- or intracellular siderophores, culture supernatants or lyophilized mycelia were saturated with FeSO 4 and extracted as described previously [18]. To analyse biomass production, mycelia from liquid cultures were freeze-dried and weighed.…”

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…The iron metabolism regulators HapX and SreA have been found to play a role in hypoxia adaptation. 83,84 Most recently, the signal peptide peptidase SppA, the protease RbdA, and the hypoxia-induced dehydrogenase HorA have also been linked to hypoxia adaptation and virulence, possibly through interactions with the Srb pathways. 80,85,86 Together these data suggest a model whereby the ability of A. fumigatus to thrive in hypoxic microenvironments is a critical factor in the pathogenesis of IA and suggest a potential role for hyperbaric oxygen therapy for IA in HSCT patients.…”