Phenol soluble modulin alpha alters the cell cycle of eukaryotic cells.

Staphylococcus aureus (SA) is a Gram-positive bacterium responsible for a wide range of infections in humans and animals. We previously demonstrated that SA USA400 MW2 strain induces a G2/M phase delay in human HeLa cells. This phenomenon was associated with the accumulation of the cyclin-dependent kinase Cdk1/cdc2 and with the accumulation of unphosphorylated histone H3. Additionally we showed that the G2 phase was preferential for staphylococcal internalization and intracellular replication (1).The objectives of the study were -to identify the active substances, which are responsible for the cell cycle alteration, -to understand, how this alteration hijacks defense functions of the host cells.Using size exclusion chromatography of MW2 supernatant, followed by mass spectroscopy analysis, we identified phenol-soluble modulin alpha (PSMα) peptides as the likely candidates for this effect. Indeed, synthetic PSMα1 and PSMα3 caused a G2/M phase transition delay. The implication of PSMα in cell cycle alteration was confirmed by comparison of wild type SA USA300 (strain LAC wt) with the isogenic mutant (LAC∆psmα), lacking the psmα operon that encodes PSMα1 to 4, for its internalization efficiency in HeLa cells. The decreased internalization rate of LAC∆psmα suggested a role of PSMα in host cell invasion. Furthermore, PSMα-induced G2/M-transition delay correlated with a decrease in the defensin genes expression suggesting a diminution of antibacterial functions of epithelial cells (2). Our results open new perspectives for the investigation of the mechanisms of the SA infection