The Journal of Experimental Medicine
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Published online 25 October 2004 doi:10.1084/jem.20041242
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 9, 1213-1219
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Brief Definitive Report

 Siderophore Biosynthesis But Not Reductive Iron Assimilation Is Essential for Aspergillus fumigatus Virulence

Markus Schrettl1, Elaine Bignell2, Claudia Kragl1, Chistoph Joechl1, Tom Rogers2, Herbert N. Arst, Jr.2, Ken Haynes2, and Hubertus Haas1

1 Department of Molecular Biology, Medical University Innsbruck, Peter-Mayr-Str. 4b/III, A-6020 Innsbruck, Austria
2 Department of Infectious Diseases, Imperial College London, London W12 0NN, England, UK

Address correspondence to Hubertus Haas, Dept. of Molecular Biology, Medical University Innsbruck, Peter-Mayr-Str. 4b/III, A-6020 Innsbruck, Austria. Phone: 43-512-507-3605; Fax: 43-512-507-9880; email: hubertus.haas{at}uibk.ac.at

The ability to acquire iron in vivo is essential for most microbial pathogens. Here we show that Aspergillus fumigatus does not have specific mechanisms for the utilization of host iron sources. However, it does have functional siderophore-assisted iron mobilization and reductive iron assimilation systems, both of which are induced upon iron deprivation. Abrogation of reductive iron assimilation, by inactivation of the high affinity iron permease (FtrA), has no effect on virulence in a murine model of invasive aspergillosis. In striking contrast, A. fumigatus L-ornithine-N 5-monooxygenase (SidA), which catalyses the first committed step of hydroxamate-type siderophore biosynthesis, is absolutely essential for virulence. Thus, A. fumigatus SidA is an essential virulence attribute. Combined with the absence of a sidA ortholog—and the fungal siderophore system in general—in mammals, these data demonstrate that the siderophore biosynthetic pathway represents a promising new target for the development of antifungal therapies.

Key Words: fungal pathogenicity • aspergillosis • iron uptake • virulence factor • ornithine monooxygenase

M. Schrettl and E. Bignell contributed equally to this work.


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