Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans

The ability of phagocytes to clear pathogens is an essential attribute of the innate immune response. The role of signaling lipid molecules such as phosphoinositides is well established, but the role of membrane sphingolipids in phagocytosis is largely unknown. Using a genetic approach and small mol...

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Bibliographic Details
Published in:PLoS pathogens 2015-10, Vol.11 (10), p.e1005188-e1005188
Main Authors: Tafesse, Fikadu G, Rashidfarrokhi, Ali, Schmidt, Florian I, Freinkman, Elizaveta, Dougan, Stephanie, Dougan, Michael, Esteban, Alexandre, Maruyama, Takeshi, Strijbis, Karin, Ploegh, Hidde L
Format: Article
Language:English
Subjects:
Animals
Biosynthesis
Candida albicans
Candida albicans - immunology
Candidiasis - immunology
Cell Line
Chromatography, Thin Layer
Dendritic cells
Dendritic Cells - immunology
Dendritic Cells - microbiology
Disease Models, Animal
Experiments
Flow Cytometry
Gangliosides
Gene Knockout Techniques
Genetic aspects
Host-Pathogen Interactions - immunology
Humans
Immune system
Lipids
Mass Spectrometry
Mice
Microscopy
Phagocytosis - physiology
Physiological aspects
Sphingolipids - biosynthesis
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Summary:The ability of phagocytes to clear pathogens is an essential attribute of the innate immune response. The role of signaling lipid molecules such as phosphoinositides is well established, but the role of membrane sphingolipids in phagocytosis is largely unknown. Using a genetic approach and small molecule inhibitors, we show that phagocytosis of Candida albicans requires an intact sphingolipid biosynthetic pathway. Blockade of serine-palmitoyltransferase (SPT) and ceramide synthase-enzymes involved in sphingolipid biosynthesis- by myriocin and fumonisin B1, respectively, impaired phagocytosis by phagocytes. We used CRISPR/Cas9-mediated genome editing to generate Sptlc2-deficient DC2.4 dendritic cells, which lack serine palmitoyl transferase activity. Sptlc2-/- DC2.4 cells exhibited a stark defect in phagocytosis, were unable to bind fungal particles and failed to form a normal phagocytic cup to engulf C. albicans. Supplementing the growth media with GM1, the major ganglioside present at the cell surface, restored phagocytic activity of Sptlc2-/- DC2.4 cells. While overall membrane trafficking and endocytic pathways remained functional, Sptlc2-/- DC2.4 cells express reduced levels of the pattern recognition receptors Dectin-1 and TLR2 at the cell surface. Consistent with the in vitro data, compromised sphingolipid biosynthesis in mice sensitizes the animal to C. albicans infection. Sphingolipid biosynthesis is therefore critical for phagocytosis and in vivo clearance of C. albicans.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005188