Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans

Fikadu Tafesse, Ali Rashidfarrokhi, Florian I. Schmidt, Elizaveta Freinkman, Stephanie Dougan, Michael Dougan, Alexandre Esteban, Takeshi Maruyama, Karin Strijbis, Hidde L. Ploegh

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005188
JournalPLoS Pathogens
Volume11
Issue number10
DOIs
StatePublished - 2015
Externally publishedYes

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Sphingolipids
Candida albicans
Phagocytosis
Phagocytes
Serine C-Palmitoyltransferase
Clustered Regularly Interspaced Short Palindromic Repeats
G(M1) Ganglioside
Pattern Recognition Receptors
Membranes
Biosynthetic Pathways
Transferases
Phosphatidylinositols
Innate Immunity
Dendritic Cells
Serine
Lipids
Enzymes
Growth
Infection

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Tafesse, F., Rashidfarrokhi, A., Schmidt, F. I., Freinkman, E., Dougan, S., Dougan, M., ... Ploegh, H. L. (2015). Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. PLoS Pathogens, 11(10), [e1005188]. https://doi.org/10.1371/journal.ppat.1005188

Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. / Tafesse, Fikadu; Rashidfarrokhi, Ali; Schmidt, Florian I.; Freinkman, Elizaveta; Dougan, Stephanie; Dougan, Michael; Esteban, Alexandre; Maruyama, Takeshi; Strijbis, Karin; Ploegh, Hidde L.

In: PLoS Pathogens, Vol. 11, No. 10, e1005188, 2015.

Research output: Contribution to journalArticle

Tafesse, F, Rashidfarrokhi, A, Schmidt, FI, Freinkman, E, Dougan, S, Dougan, M, Esteban, A, Maruyama, T, Strijbis, K & Ploegh, HL 2015, 'Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans', PLoS Pathogens, vol. 11, no. 10, e1005188. https://doi.org/10.1371/journal.ppat.1005188
Tafesse F, Rashidfarrokhi A, Schmidt FI, Freinkman E, Dougan S, Dougan M et al. Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. PLoS Pathogens. 2015;11(10). e1005188. https://doi.org/10.1371/journal.ppat.1005188
Tafesse, Fikadu ; Rashidfarrokhi, Ali ; Schmidt, Florian I. ; Freinkman, Elizaveta ; Dougan, Stephanie ; Dougan, Michael ; Esteban, Alexandre ; Maruyama, Takeshi ; Strijbis, Karin ; Ploegh, Hidde L. / Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans. In: PLoS Pathogens. 2015 ; Vol. 11, No. 10.
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