Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence.
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-N5-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.
Schrettl
Markus
M
Dept. of Molecular Biology, Medical University Innsbruck, Peter-Mayr-Str. 4b/III, A-6020 Innsbruck, Austria. hubertus.haas@uibk.ac.at.
Bignell
Elaine
E
Kragl
Claudia
C
Joechl
Chistoph
C
Rogers
Tom
T
Arst
Herbert N
HN
Haynes
Ken
K
Haas
Hubertus
H
D000818:Animals; D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000378:metabolism / Q000472:pathogenicity*; D001483:Base Sequence; D015152:Blotting, Northern; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017262:Siderophores / Q000096:biosynthesis*
D017931:DNA Primers; D018076:DNA, Complementary; D005656:Fungal Proteins; D017262:Siderophores; D007501:Iron; D006899:Mixed Function Oxygenases; C059419:ornithine N5-oxygenase