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 ΔsidA, 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.
Highlights
Animals strategically withhold iron during infection to combat invading microbes [1,2]
The microbial quest for iron in mammalian hosts is crucial for successful pathogenesis as, in this environment, iron is tightly bound by carrier proteins such as transferrin, leaving free iron concentrations insufficient for sustenance of microbial growth
Most aerobic bacteria and fungi have genes encoding iron transport systems that become induced under iron limitation [30,31], among which siderophoremediated iron transport provides a means of uptake, even for organisms which cannot themselves synthesize such molecules
Summary
Animals strategically withhold iron during infection to combat invading microbes [1,2]. Patients with suppressed immune systems due to cancer treatments, HIV/AIDS, organ transplantation, or genetic disorders are at high risk of infection with the ubiquitously present fungal pathogen Aspergillus fumigatus. Treatments for this disease, collectively termed invasive aspergillosis, are often not successful, and prospects for survival can be slim. A. fumigatus produces small molecules, termed siderophores, for acquisition and storage of iron, an element essential for growth. We found that these siderophores are crucial for virulence of A. fumigatus because their removal (by gene deletion) prevents or lessens disease in a mouse model of invasive aspergillosis. With respect to its two-module structure and amino acid sequence, SidD
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