Iron homeostasis-maintainance in Aspergillus fumigatus

Members of the genus Aspergillus are found ubiquitously in nature. Despite the fact that Aspergilli are typical saprophytic organisms and that humans inhale hundreds of their conidia daily without consequences, as opportunists these fungi are responsible for a wide spectrum of diseases from allergies to invasive aspergillosis. In particular, invasive aspergillosis represents a life-threatening disease of increasing incidence in immunocompromised patients since there are only a limited number of antimycotic drugs available. For the development of novel antifungal agents the precise knowledge of the fungal metabolism is needed. Since iron is tightly sequestered in mammalian hosts by high-affinity iron-binding proteins - e.g. ferritine, lactoferrin, and transferrin - microbes face iron starvation during infection and require efficient iron-scavenging systems to "steal" the iron from the host. Recently we have shown that the siderophore system is absolutely essential for virulence of Aspergillus fumigatus. Siderophores are low molecular mass peptides with extremely high binding affinity to iron. Most fungi excrete these iron chelators to mobilize extracellular iron and additionally use siderophores to store iron intracellularly. As mammals lack the siderophore system, it is a promising new target for development of antifungal therapies. Employing microarray-based genome-wide expression profiling, we have recently identified those genes, the expression of which is affected by iron availability indicating their involvement iron acquisition or general adaption to iron starvation. The goal of the current grant proposal is to analyze the function of the identified genes and their role in iron homeostasis and virulence of A. fumigatus. The detailed study of the fungal siderophore system is not only highly interesting from a basic science view but also serves to further evaluate this system as a target for antifungal therapy to advance treatment of fungal infections.

Members of the mold genus Aspergillus are found ubiquitously in nature. Despite the fact that Aspergilli are typical saprophytic organisms and that humans inhale hundreds of their conidia daily without consequences, as opportunists these fungi are responsible for a wide spectrum of diseases from allergies to invasive aspergillosis. In particular, invasive aspergillosis represents a life-threatening disease of increasing incidence in immunocompromised patients due to limited therapeutic and diagnostic possibilities. The improvement of antifungal therapy and diagnosis requires detailed characterization of the fungal metabolism. Since iron is tightly sequestered in mammalian hosts by high-affinity iron-binding proteins - e.g. ferritin, lactoferrin, and transferrin - microbes face iron starvation during infection and require efficient iron-scavenging systems to steal the iron from the host. Previously, we have shown that the siderophore system is absolutely essential for virulence of Aspergillus fumigatus. Siderophores are low molecular-mass, ferric iron-specific chelators, which are secreted by most fungi to mobilize extracellular iron and are additionally used to store and transport iron intracellularly. As mammals lack the siderophore system, it is a promising new target for development of antifungal therapies. Using genome-wide transcriptional profiling, we identified A. fumigatus genes, the expression of which is affected by iron availability indicating their involvement in iron homeostasis. The functional analysis of the identified genes resulted in a detailed characterization of fungal iron homeostasis. We identified and characterized cellular components that are involved in iron regulation, siderophore biosynthesis, intracellular siderophore degradation, reductive iron assimilation and vacuolar iron storage. Siderophore biosynthesis was found to be partially localized in peroxisomes, and linked at enzymatic and regulatory levels with amino acid metabolism as well as biosynthesis of polyamines and sterols. Moreover our studies underline the promising potential of siderophores labeled with the isotope 68Gallium for in vivo PET (positron emission tomography)-imaging of aspergillosis.