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The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA, Encoding L-Ornithine N⁵-Oxygenase, Is Required for Virulence

Hissen, Anna H. T., Wan, Adrian N. C., Warwas, Mark L., Pinto, Linda J., Moore, Margo M.
Infection and immunity 2005 v.73 no.9 pp. 5493-5503
Aspergillus fumigatus, amino acids, animal models, aspergillosis, biosynthesis, blood serum, fungi, genes, humans, immunocompromised population, iron, secretion, siderophores, transferrin, virulence
Aspergillus fumigatus is the leading cause of invasive mold infection and is a serious problem in immunocompromised populations worldwide. We have previously shown that survival of A. fumigatus in serum may be related to secretion of siderophores. In this study, we identified and characterized the sidA gene of A. fumigatus, which encodes L-ornithine N⁵-oxygenase, the first committed step in hydroxamate siderophore biosynthesis. A. fumigatus sidA codes for a protein of 501 amino acids with significant homology to other fungal L-ornithine N⁵-oxygenases. A stable [Delta]sidA strain was created by deletion of A. fumigatus sidA. This strain was unable to synthesize the siderophores N',N",N'''-triacetylfusarinine C (TAF) and ferricrocin. Growth of the [Delta]sidA strain was the same as that of the wild type in rich media; however, the [Delta]sidA strain was unable to grow in low-iron defined media or media containing 10% human serum unless supplemented with TAF or ferricrocin. No significant differences in ferric reduction activities were observed between the parental strain and the [Delta]sidA strain, indicating that blocking siderophore secretion did not result in upregulation of this pathway. Unlike the parental strain, the [Delta]sidA strain was unable to remove iron from human transferrin. A rescued strain ([Delta]sidA + sidA) was constructed; it produced siderophores and had the same growth as the wild type on iron-limited media. Unlike the wild-type and rescued strains, the [Delta]sidA strain was avirulent in a mouse model of invasive aspergillosis, indicating that sidA is necessary for A. fumigatus virulence.