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.

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

“…The fungal pathogen Aspergillus fumigatus produces four hydroxamate siderophores: fusarinine C and triacetylfusarinine C, which are secreted, and ferricrocin the intracellular iron storage siderophore in hyphae and hydroxyferricrocin the iron siderophore storage in conidial spores (Schrettl et al, 2007;Wallner et al, 2009;Haas, 2012). An additional siderophore-like molecule called hexadeydroastechrome was recently isolated from Aspergillus fumigatus and increased virulence when overexpressed in a murine model of infection (Yin et al, 2013).…”

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

“…To survive in the human host under conditions of iron starvation, A. fumigatus employs two high-affinity iron-uptake systems, reductive iron assimilation and the extracellular siderophores fusarinine C (FsC) and triacetylfusarinine C (TAFC), as well as the intracellular siderophore ferricrocin (FC) for iron storage and distribution [26,27]. To further characterize the role of riboflavin biosynthesis in iron utilization and siderophore production, wt and Δ riboB were analysed after growth in liquid minimal medium during iron starvation (-Fe), iron sufficiency (+Fe, 30 µM FeSO 4 ) and iron excess (hFe, 5 mM FeSO 4 ) supplemented with either a low (0.1 µM) or a high (2.5 µM) riboflavin concentration (Figure 4).…”

Biomarkers for Invasive Aspergillosis: The Challenges Continue

“…Iron, an indispensable cofactor for many cellular processes including electron transport, amino acid metabolism and biosynthesis of DNA, is a key nutrient for most organisms, including Aspergillus [113]. However, since iron excess or incorrect storage can catalyze the formation of reactive oxygen species, Aspergillus has evolved complex mechanisms to balance its acquisition, storage and consumption [113].…”

“…However, since iron excess or incorrect storage can catalyze the formation of reactive oxygen species, Aspergillus has evolved complex mechanisms to balance its acquisition, storage and consumption [113]. Under iron-limited conditions one strategy involves the biosynthesis of siderophores, which are low molecular mass iron chelators that acquire iron from the environment [114] (Figure 5).…”