The stearoyl-coenzyme A desaturase 1 is essential for virulence and membrane stress in Candida parapsilosis through unsaturated fatty acid production.
Unsaturated fatty acids (UFA) are essential components of cells. In Saccharomyces cerevisiae, stearoyl-coenzyme A (CoA) desaturase 1 (OLE1) affects cell viability through the regulation of oleic (18:1) or palmitoleic (16:1) acid production. In this study, we used a targeted gene deletion approach to determine the impact of OLE1 on the emerging human pathogenic fungus Candida parapsilosis. We found that the deletion of OLE1 resulted in an auxotrophic yeast strain (designated OLE1 KO) that required unsaturated fatty acids for growth but not saturated fatty acids. Additionally, the production of UFA by OLE1 KO yeast cells was markedly reduced, suggesting that Ole1 is essential for UFA production. In contrast to wild-type C. parapsilosis, which produced pseudohyphal growth on UFA-supplemented medium agar, pseudohyphal formation in the OLE1 KO cells was severely impaired, suggesting that Ole1 regulates morphology. Furthermore, the OLE1 KO cells were hypersensitive to various stress-inducing factors, such as salts, SDS, and H(2)O(2), especially at the physiological temperature. The results indicate that OLE1 is essential for the stress response, perhaps through the production of UFA for cell membrane biosynthesis. The OLE1 KO cells also were hypersensitive to human and fetal bovine serum, suggesting that targeting Ole1 could suppress the dissemination of yeast cells in the bloodstream. Murine-like macrophage J774.16 more efficiently killed the OLE1 KO yeasts, and significantly larger amounts of nitric oxide were detected in cocultures of macrophages and OLE1 KO cells than with wild-type or heterozygous strains. Moreover, the disruption of OLE1 significantly reduced fungal virulence in systemic murine infection. Taken together, these results demonstrate that Ole1 regulates the pathobiology of C. parapsilosis via UFA and that the OLE1 pathway is a promising antifungal target.
Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, 1300 Morris Park Ave., New York, New York 10461, USA.
Long Nam
LN
Nguyen
Attila
A
Gacser
Joshua D
JD
Nosanchuk
D000818:Animals; D002175:Candida / Q000201:enzymology* / Q000472:pathogenicity*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology*; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D010587:Phagocytosis; D013230:Stearoyl-CoA Desaturase; D013312:Stress, Physiological; D014774:Virulence
D005231:Fatty Acids, Unsaturated; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase