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Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans.

Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans.

Authors :
Tafesse FG
Rashidfarrokhi A
Schmidt FI
Freinkman E
Dougan S
Dougan M
Esteban A
Maruyama T
Strijbis K
Ploegh HL
Source :
PLoS pathogens [PLoS Pathog] 2015 Oct 02; Vol. 11 (10), pp. e1005188. Date of Electronic Publication: 2015 Oct 02 (Print Publication: 2015).
Publication Year :
2015

Abstract

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.

Details

Language :
English
ISSN :
1553-7374
Volume :
11
Issue :
10
Database :
MEDLINE
Journal :
PLoS pathogens
Publication Type :
Academic Journal
Accession number :
26431038
Full Text :
https://doi.org/10.1371/journal.ppat.1005188