Aspergillus fumigatus siderophores and virulence

Members of the genus Aspergillus are found ubiquitously in nature. Despite the fact that Aspergilli are typical saprophytic organisms, 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 metabolism of this fungus is needed. Since iron is tightly sequestered in mammalian hosts by high-affinity iron-binding proteins - e.g. hemoglobin, ferritine, and transferrin - microbes 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 several putative new genes involved in siderophore metabolism of A. fumigatus. The goal of the current grant proposal is to analyze the function of the identified genes and their role in virulence of A. fumigatus as well as to determine the subcellular localization of the siderophore system. 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 genus Aspergillus are found ubiquitously in nature. Despite the fact that Aspergilli are typical saprophytic organisms, 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 metabolism of this fungus is needed. Since iron is tightly sequestered in mammalian hosts by high-affinity iron-binding proteins - e.g. hemoglobin, ferritine, and transferrin - microbes 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 several putative new genes involved in siderophore metabolism of A. fumigatus. The goal of the current grant proposal is to analyze the function of the identified genes and their role in virulence of A. fumigatus as well as to determine the subcellular localization of the siderophore system. 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.