Fatty acid synthase impacts the pathobiology of Candida parapsilosis in vitro and during mammalian infection.
Cytosolic fungal fatty acid synthase is composed of two subunits alpha and beta, which are encoded by Fas1 and Fas2 genes. In this study, the Fas2 genes of the human pathogen Candida parapsilosis were deleted using a modified SAT1 flipper technique. CpFas2 was essential in media lacking exogenous fatty acids and the growth of Fas2 disruptants (Fas2 KO) was regulated by the supplementation of different long chain fatty acids, such as myristic acid (14ratio0), palmitic acid (16ratio0), and Tween 80, in a dose-specific manner. Lipidomic analysis revealed that Fas2 KO cells were severely restricted in production of unsaturated fatty acids. The Fas2 KO strains were unable to form normal biofilms and were more efficiently killed by murine-like macrophages, J774.16, than the wild type, heterozygous and reconstituted strains. Furthermore, Fas2 KO yeast were significantly less virulent in a systemic murine infection model. The Fas2 KO cells were also hypersensitive to human serum, and inhibition of CpFas2 in WT C. parapsilosis by cerulenin significantly decreased fungal growth in human serum. This study demonstrates that CpFas2 is essential for C. parapsilosis growth in the absence of exogenous fatty acids, is involved in unsaturated fatty acid production, influences fungal virulence, and represents a promising antifungal drug target.
Nguyen
Long Nam
LN
Department of Medicine (Division of Infectious Diseases), Albert Einstein College of Medicine, New York, New York, USA.
Trofa
David
D
Nosanchuk
Joshua D
JD
D000818:Animals; D018441:Biofilms / Q000187:drug effects; D002175:Candida / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D002177:Candidiasis / Q000201:enzymology* / Q000382:microbiology*; D002244:Carbon / Q000494:pharmacology; D003470:Culture Media; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D044967:Serum; D013312:Stress, Physiological / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D003470:Culture Media; D005227:Fatty Acids; D002244:Carbon; D064429:Fatty Acid Synthases