Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of
The fungus Candida albicans is not only a commensal of the digestive system, but also a common cause of human opportunistic infections. Macrophages and dendritic cells can eliminate C. albicans by phagocytosis, a complex process that involves extensive membrane reorganization at the cell surface. The extent to which membrane lipids, including sphingolipids, contribute to the proper execution of phagocytosis remains largely unknown. Pharmacological blockade of sphingolipid biosynthesis by the small molecule inhibitors myriocin and fumonisin B1 impairs phagocytosis of C. albicans. DC2.4 dendritic cells genetically deficient in Sptlc2, the enzyme that catalyzes the first and rate-limiting step in the sphingolipid biosynthetic pathway, are likewise defective in phagocytosis of C. albicans. Sptlc2-/- DC2.4 cells showed reduced binding of C. albicans, but overall membrane transport and protein secretion remained functional. Sptlc2-deficient cells express reduced levels of the receptors Dectin-1 and TLR2 at the cell surface, and are unable to form a normal phagocytic cup. Exogenous addition of the major ganglioside GM1 restored phagocytic ability of Sptlc2-/- DC2.4 cells. Mice with compromised sphingolipid production upon in vivo treatment with fumonisin B1 fail to eradicate C. albicans, consistent with the in vitro results. Sphingolipids are thus essential for clearance of fungal infection through phagocytosis, and hence indispensable for the proper functioning of the innate immune system.
Vyšlo v časopise:
Disruption of Sphingolipid Biosynthesis Blocks Phagocytosis of. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005188
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Research Article
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https://doi.org/10.1371/journal.ppat.1005188
Souhrn
The fungus Candida albicans is not only a commensal of the digestive system, but also a common cause of human opportunistic infections. Macrophages and dendritic cells can eliminate C. albicans by phagocytosis, a complex process that involves extensive membrane reorganization at the cell surface. The extent to which membrane lipids, including sphingolipids, contribute to the proper execution of phagocytosis remains largely unknown. Pharmacological blockade of sphingolipid biosynthesis by the small molecule inhibitors myriocin and fumonisin B1 impairs phagocytosis of C. albicans. DC2.4 dendritic cells genetically deficient in Sptlc2, the enzyme that catalyzes the first and rate-limiting step in the sphingolipid biosynthetic pathway, are likewise defective in phagocytosis of C. albicans. Sptlc2-/- DC2.4 cells showed reduced binding of C. albicans, but overall membrane transport and protein secretion remained functional. Sptlc2-deficient cells express reduced levels of the receptors Dectin-1 and TLR2 at the cell surface, and are unable to form a normal phagocytic cup. Exogenous addition of the major ganglioside GM1 restored phagocytic ability of Sptlc2-/- DC2.4 cells. Mice with compromised sphingolipid production upon in vivo treatment with fumonisin B1 fail to eradicate C. albicans, consistent with the in vitro results. Sphingolipids are thus essential for clearance of fungal infection through phagocytosis, and hence indispensable for the proper functioning of the innate immune system.
Zdroje
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