Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of Candida albicans

PLoS Pathogens

Ali Rashidfarrokhi¹  Elizaveta Freinkman¹  Karin Strijbis²  Florian I. Schmidt²  Hidde L. Ploegh²  Alexandre Esteban²  Michael Dougan²  Takeshi Maruyama²  Stephanie Dougan²  Fikadu G. Tafesse² 

[1] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America;Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America

关键词: Sphingolipids;    Phagocytosis;    C;    ida albicans;    Lipids;    Cell membranes;    Biosynthesis;    Phagocytes;    Membrane proteins;   

DOI  :  10.1371/journal.ppat.1005188

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY