Role of phospholipomannan in Candida albicans escape from macrophages and induction of cell apoptosis through regulation of bad phosphorylation.
Candida albicans, the most common opportunistic fungal pathogen of humans is a part of the normal microbial flora. To investigate host-parasite interaction related to the commensal-pathogen switch of this yeast we compared the response of macrophages to C. albicans and to the non-pathogenic yeast Saccharomyces cerevisiae. In contrast to S. cerevisiae, C. albicans survived within macrophages. This escape from macrophages was associated with qualitative differences in the sequential phosphorylation of MEK, ERK1/2, and p90RSK during phagocytosis. Decreased activation of this pathway was observed with C. albicans and was associated with a species-specific overexpression of the MEK phosphatase, MKP-1. Dysregulation of the ERK1/2/p90RSK signal transduction pathway by C. albicans was associated downstream with reduction in Bad phosphorylation, specifically at Ser-112, and disappearance of free Bcl-2. This ended at apoptosis of cells that have ingested C. albicans, as revealed by staining of phosphatidylserine exposure in the macrophage outer membrane. The role of phospholipomannan (PLM), a phylogenetically unique glycolipid with a phytoceramide moiety expressed at the surface of and shed by C. albicans, was examined. Addition of PLM to macrophages led to dysregulation similar to that observed with live C. albicans and promoted the survival of the sensitive S. cerevisiae within the cells. Evidence of externalization of membranous phosphatidylserine, loss of mitochondrial integrity, and DNA fragmentation after incubation of macrophages with PLM suggest that this molecule supported the activities observed with C. albicans yeast cells.
Ibata-Ombetta
Stella
S
Laboratoire de Mycologie Fondamentale et Appliquée, Inserm EMI0360, Université de Lille II, 59037 Lille Cedex, France.
Idziorek
Thierry
T
Trinel
Pierre-André
PA
Poulain
Daniel
D
Jouault
Thierry
T
D000818:Animals; D002176:Candida albicans / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D006017:Glycolipids / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000382:microbiology* / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000502:physiology; D015398:Signal Transduction; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D002352:Carrier Proteins; D006017:Glycolipids; D051025:bcl-Associated Death Protein; C400188:phospholipomannan