title: Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection.
abstract: Siderophore biosynthesis by the highly lethal mould Aspergillus fumigatus is essential for virulence, but non-existent in humans, presenting a rare opportunity to strategize therapeutically against this pathogen. We have previously demonstrated that A. fumigatus excretes fusarinine C and triacetylfusarinine C to capture extracellular iron, and uses ferricrocin for hyphal iron storage. Here, we delineate pathways of intra- and extracellular siderophore biosynthesis and show that A. fumigatus synthesizes a developmentally regulated fourth siderophore, termed hydroxyferricrocin, employed for conidial iron storage. By inactivation of the nonribosomal peptide synthetase SidC, we demonstrate that the intracellular siderophores are required for germ tube formation, asexual sporulation, resistance to oxidative stress, catalase A activity, and virulence. Restoration of the conidial hydroxyferricrocin content partially rescues the virulence of the apathogenic siderophore null mutant Delta sidA, demonstrating an important role for the conidial siderophore during initiation of infection. Abrogation of extracellular siderophore biosynthesis following inactivation of the acyl transferase SidF or the nonribosomal peptide synthetase SidD leads to complete dependence upon reductive iron assimilation for growth under iron-limiting conditions, partial sensitivity to oxidative stress, and significantly reduced virulence, despite normal germ tube formation. Our findings reveal distinct cellular and disease-related roles for intra- and extracellular siderophores during mammalian Aspergillus infection.
authors.affiliation: Biocenter-Divison of Molecular Biology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Schrettl
authors.forename: Elaine
authors.initials: E
authors.lastname: Bignell
authors.forename: Claudia
authors.initials: C
authors.lastname: Kragl
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Sabiha
authors.forename: Omar
authors.initials: O
authors.lastname: Loss
authors.forename: Martin
authors.initials: M
authors.lastname: Eisendle
authors.forename: Anja
authors.initials: A
authors.lastname: Wallner
authors.forename: Herbert N
authors.initials: HN
authors.lastname: Arst
authors.forename: Ken
authors.initials: K
authors.lastname: Haynes
authors.forename: Hubertus
authors.initials: H
authors.lastname: Haas
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000503:physiopathology*; D001232:Aspergillus fumigatus / Q000378:metabolism / Q000472:pathogenicity*; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000502:physiology; D017262:Siderophores / Q000502:physiology*; D013172:Spores, Fungal / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence
chemical_list: D017262:Siderophores; D007501:Iron