Iron - A Key Nexus in the Virulence of Aspergillus fumigatus

Abstract

Iron is an essential but, in excess, toxic nutrient. Therefore, fungi evolved fine-tuned mechanisms for uptake and storage of iron, such as the production of siderophores (low-molecular mass iron-specific chelators). In Aspergillus fumigatus, iron starvation causes extensive transcriptional remodeling involving two central transcription factors, which are interconnected in a negative transcriptional feed-back loop: the GATA-factor SreA and the bZip-factor HapX. During iron sufficiency, SreA represses iron uptake, including reductive iron assimilation and siderophore-mediated iron uptake, to avoid toxic effects. During iron starvation, HapX represses iron-consuming pathways, including heme biosynthesis and respiration, to spare iron and activates synthesis of ribotoxin AspF1 and siderophores, the latter partly by ensuring supply of the precursor, ornithine. In accordance with the expression pattern and mode of action, detrimental effects of inactivation of SreA and HapX are confined to growth during iron sufficiency and iron starvation, respectively. Deficiency in HapX, but not SreA, attenuates virulence of A. fumigatus in a murine model of aspergillosis, which underlines the crucial role of adaptation to iron limitation in virulence. Consistently, production of both extra and intracellular siderophores is crucial for virulence of A. fumigatus. Recently, the sterol regulatory element binding protein SrbA was found to be essential for adaptation to iron starvation, thereby linking regulation of iron metabolism, ergosterol biosynthesis, azole drug resistance, and hypoxia adaptation.

Keywords: ergosterol; fungi; iron; isoprenoid; mevalonate; ornithine; siderophore; virulence.

Figure 1

Siderophores produced by A. fumigatus and A. nidulans: R = H in fusarinine C (FsC) and R = acetyl in triacetylfusarinine C (TAFC); the hydroxylation site in hydroxyferricrocin (HFC) is unknown. The siderophores are shown in the ferric (Fe³⁺) form.

Figure 2

Siderophore biosynthesis (in purple) and its links to the isoprenoid biosynthesis (in green) as well as ornithine/arginine metabolism (in blue). The enzymes, boxed in respective colors, are described in the text and Table 1. Enzymatic steps transcriptionally upregulated during iron starvation are marked by red arrows. Broken arrows denote reactions involving more than one enzyme.

Figure 3

Iron regulation in Aspergillus spp. (A) Scheme of SreA- and HapX-mediated iron regulation. (B) Phenotypes of A. fumigatus SreA-(ΔsreA) and HapX-(ΔhapX) deficient mutant strains in 24 h/37°C flask cultures. In contrast to the wild type (wt), ΔhapX mycelia are reddish colored during iron starvation due to accumulation of protoporphyrin IX, while ΔsreA mycelia are reddish colored during iron sufficiency due to accumulation of iron, heme, and FC (Schrettl et al., 2008, 2010a).