دورية أكاديمية
The Candida albicans quorum-sensing molecule farnesol alters sphingolipid metabolism in human monocyte-derived dendritic cells.
| العنوان: | The Candida albicans quorum-sensing molecule farnesol alters sphingolipid metabolism in human monocyte-derived dendritic cells. |
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| المؤلفون: | Batliner M; Institute for Hygiene and Microbiology, Julius-Maximilians University of Würzburg, Würzburg, Germany., Schumacher F; Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany., Wigger D; Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany., Vivas W; Institute for Infectious Diseases and Infection Control, Jena University Hospital-Friedrich Schiller University, Jena, Germany.; Associated Research Group Translational Infection Medicine, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute (HKI), Jena, Germany.; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital-Friedrich Schiller University, Jena, Germany., Prell A; Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany., Fohmann I; Institute for Hygiene and Microbiology, Julius-Maximilians University of Würzburg, Würzburg, Germany., Köhler T; Institute for Hygiene and Microbiology, Julius-Maximilians University of Würzburg, Würzburg, Germany., Schempp R; Institute for Virology and Immunobiology, Julius-Maximilians University of Würzburg, Würzburg, Germany., Riedel A; Mildred Scheel Early Career Center (MSNZ), University Hospital of Würzburg, Würzburg, Germany., Vaeth M; Max Planck Research Group, Würzburg Institute of Systems Immunology, Julius-Maximilians University of Würzburg, Würzburg, Germany., Fekete A; Pharmaceutical Biology, Julius-von-Sachs-Institute, Biocenter, University of Würzburg, Würzburg, Germany., Kleuser B; Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany., Kurzai O; Institute for Hygiene and Microbiology, Julius-Maximilians University of Würzburg, Würzburg, Germany.; Research Group Fungal Septomics, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.; National Reference Center for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany., Nieuwenhuizen NE; Institute for Hygiene and Microbiology, Julius-Maximilians University of Würzburg, Würzburg, Germany. |
| المصدر: | MBio [mBio] 2024 Aug 14; Vol. 15 (8), pp. e0073224. Date of Electronic Publication: 2024 Jul 02. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Farnesol*/pharmacology , Farnesol*/metabolism , Dendritic Cells*/drug effects , Dendritic Cells*/metabolism , Dendritic Cells*/immunology , Candida albicans*/drug effects , Candida albicans*/metabolism , Sphingolipids*/metabolism , Quorum Sensing*/drug effects , Monocytes*/metabolism , Monocytes*/drug effects , Monocytes*/microbiology , Monocytes*/immunology, Humans ; PPAR gamma/metabolism ; PPAR gamma/genetics ; Tandem Mass Spectrometry ; Cytokines/metabolism |
| مستخلص: | Candida albicans, an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human monocyte-derived dendritic cells (DCs), including their cytokine secretion and ability to prime T cells. This is partially dependent on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which has numerous ligands, including the sphingolipid metabolite sphingosine 1-phosphate. Sphingolipids are a vital component of membranes that affect membrane protein arrangement and phagocytosis of C. albicans by DCs. Thus, we quantified sphingolipid metabolites in monocytes differentiating into DCs by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Farnesol increased the activity of serine palmitoyltransferase, leading to increased levels of 3-keto-dihydrosphingosine, dihydrosphingosine, and dihydrosphingosine 1-phosphate and inhibited dihydroceramide desaturase by inducing oxidative stress, leading to increased levels of dihydroceramide and dihydrosphingomyelin species and reduced ceramide levels. Accumulation of dihydroceramides can inhibit mitochondrial function; accordingly, farnesol reduced mitochondrial respiration. Dihydroceramide desaturase inhibition increases lipid droplet formation, which we observed in farnesol-treated cells, coupled with an increase in intracellular triacylglycerol species. Furthermore, inhibition of dihydroceramide desaturase with either farnesol or specific inhibitors impaired the ability of DCs to prime interferon-γ-producing T cells. The effect of farnesol on sphingolipid metabolism, triacylglycerol synthesis, and mitochondrial respiration was not dependent on PPAR-γ. In summary, our data reveal novel effects of farnesol on sphingolipid metabolism, neutral lipid synthesis, and mitochondrial function in DCs that affect their instruction of T cell cytokine secretion, indicating that C. albicans can manipulate host cell metabolism via farnesol secretion.IMPORTANCE Candida albicans is a common commensal yeast, but it is also an opportunistic pathogen which is one of the leading causes of potentially lethal hospital-acquired infections. There is growing evidence that its overgrowth in the gut can influence diseases as diverse as alcohol-associated liver disease and COVID-19. Previously, we found that its quorum-sensing molecule, farnesol, alters the phenotype of dendritic cells differentiating from monocytes, impairing their ability to drive protective T cell responses. Here, we demonstrate that farnesol alters the metabolism of sphingolipids, important structural components of the membrane that also act as signaling molecules. In monocytes differentiating to dendritic cells, farnesol inhibited dihydroceramide desaturase, resulting in the accumulation of dihydroceramides and a reduction in ceramide levels. Farnesol impaired mitochondrial respiration, known to occur with an accumulation of dihydroceramides, and induced the accumulation of triacylglycerol and oil bodies. Inhibition of dihydroceramide desaturase resulted in the impaired ability of DCs to induce interferon-γ production by T cells. Thus, farnesol production by C. albicans could manipulate the function of dendritic cells by altering the sphingolipidome. Competing Interests: The authors declare no conflict of interest. |
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| معلومات مُعتمدة: | 417857878 Deutsche Forschungsgemeinschaft (DFG); 492620490 Deutsche Forschungsgemeinschaft (DFG); 210879364 Deutsche Forschungsgemeinschaft (DFG) |
| فهرسة مساهمة: | Keywords: Candida albicans; dendritic cells; dihydroceramide; dihydroceramide desaturase; farnesol; fungi; mitochondrial metabolism; monocytes; oxidative stress; quorum-sensing; serine palmitoyltransferase; sphingolipids |
| المشرفين على المادة: | 4602-84-0 (Farnesol) 0 (Sphingolipids) 0 (PPAR gamma) 0 (Cytokines) |
| تواريخ الأحداث: | Date Created: 20240702 Date Completed: 20240814 Latest Revision: 20240816 |
| رمز التحديث: | 20240816 |
| مُعرف محوري في PubMed: | PMC11323541 |
| DOI: | 10.1128/mbio.00732-24 |
| PMID: | 38953353 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mbio.00732-24 |