Aspergillus fumigatus is the most common human airborne mold pathogen. Adaptation to iron starvation includes down-regulation of iron-consuming pathways to spare iron and up-regulation of high-affinity iron acquisition mechanisms including reductive iron assimilation and siderophore-mediated iron acquisition. The transcription factors SreA, HapX, SrbA and LeuB play central roles in iron regulation but several lines of evidence indicate that additional mechanisms are likely to exist. Adaptation to iron starvation is particularly crucial during invasive growth in the host, which represents a niche with limited iron access. In this regard, siderophore biosynthesis, HapX and SrbA have been shown to be crucial for virulence of A. fumigatus as well as for other animal- and plant-pathogenic fungi, which reflects the central role of iron metabolism in fungal physiology. Moreover, the shown potential of the siderophore system for imaging of invasive aspergillosis in rodent infection models and as biomarker for invasive aspergillosis in human patients emphasize that A. fumigatus faces iron starvation during mammalian infection.
Genome-wide transcriptional profiling identified structural as well as regulatory genes, whose expression is regulated by iron and whose function in adaptation is unknown so far. We aim to functionally characterize these iron-controlled genes via gene inactivation or overexpression followed by phenotypical, biochemical and molecular analyses. Moreover, promoter motifs mediating iron regulation will be characterized by reporter gene assays. These studies will help to increase the understanding of the adaption of A. fumigatus to iron starvation and consequently the host niche.
