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Peroxisomal Fatty Acid ß-Oxidation Is Not Essential for Virulence of Candida albicans

Departments of Medical Biochemistry,¹ Genetic Metabolic Diseases, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands,² Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, Aberdeen AB25 2ZD, United Kingdom³

Received 30 March 2006/ Accepted 29 August 2006

Phagocytic cells form the first line of defense against infections by the human fungal pathogen Candida albicans. Recent in vitro gene expression data suggest that upon phagocytosis by macrophages, C. albicans reprograms its metabolism to convert fatty acids into glucose by inducing the enzymes of the glyoxylate cycle and fatty acid ß-oxidation pathway. Here, we asked whether fatty acid ß-oxidation, a metabolic pathway localized to peroxisomes, is essential for fungal virulence by constructing two C. albicans double deletion strains: a pex5/pex5 mutant, which is disturbed in the import of most peroxisomal enzymes, and a fox2/fox2 mutant, which lacks the second enzyme of the ß-oxidation pathway. Both mutant strains had strongly reduced ß-oxidation activity and, accordingly, were unable to grow on media with fatty acids as a sole carbon source. Surprisingly, only the fox2/fox2 mutant, and not the pex5/pex5 mutant, displayed strong growth defects on nonfermentable carbon sources other than fatty acids (e.g., acetate, ethanol, or lactate) and showed attenuated virulence in a mouse model for systemic candidiasis. The degree of virulence attenuation of the fox2/fox2 mutant was comparable to that of the icl1/icl1 mutant, which lacks a functional glyoxylate cycle and also fails to grow on nonfermentable carbon sources. Together, our data suggest that peroxisomal fatty acid ß-oxidation is not essential for virulence of C. albicans, implying that the attenuated virulence of the fox2/fox2 mutant is largely due to a dysfunctional glyoxylate cycle.

Published ahead of print on 8 September 2006.

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