Peroxisomal fatty acid beta-oxidation is not essential for virulence of Candida albicans.
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 beta-oxidation pathway. Here, we asked whether fatty acid beta-oxidation, a metabolic pathway localized to peroxisomes, is essential for fungal virulence by constructing two C. albicans double deletion strains: a pex5Delta/pex5Delta mutant, which is disturbed in the import of most peroxisomal enzymes, and a fox2Delta/fox2Delta mutant, which lacks the second enzyme of the beta-oxidation pathway. Both mutant strains had strongly reduced beta-oxidation activity and, accordingly, were unable to grow on media with fatty acids as a sole carbon source. Surprisingly, only the fox2Delta/fox2Delta mutant, and not the pex5Delta/pex5Delta 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 fox2Delta/fox2Delta mutant was comparable to that of the icl1Delta/icl1Delta mutant, which lacks a functional glyoxylate cycle and also fails to grow on nonfermentable carbon sources. Together, our data suggest that peroxisomal fatty acid beta-oxidation is not essential for virulence of C. albicans, implying that the attenuated virulence of the fox2Delta/fox2Delta mutant is largely due to a dysfunctional glyoxylate cycle.
Piekarska
Katarzyna
K
Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Mol
Els
E
van den Berg
Marlene
M
Hardy
Guy
G
van den Burg
Janny
J
van Roermund
Carlo
C
MacCallum
Donna
D
Odds
Frank
F
Distel
Ben
B
D015094:3-Hydroxyacyl CoA Dehydrogenases; D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity* / Q000648:ultrastructure; D002177:Candidiasis / Q000378:metabolism / Q000401:mortality; D004746:Enoyl-CoA Hydratase; D005227:Fatty Acids / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D019301:Oleic Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D004746:Enoyl-CoA Hydratase; C073759:FOX2 protein, S cerevisiae