Phenol-soluble modulins alpha induce G2/M phase transition delay and impair immune response of eukaryotic cells

Staphylococcus aureus is responsible for a wide range of infections in human and animals. We found that S aureus slowed down host cell proliferation and induced a cytopathic effect. We demonstrated that S aureus induced a G2/M phase transition delay in host cells, which was associated with accumulation of the cyclin-dependent kinase Cdk1/cdc2 and unphosphorylated histone H3. We found that a G2 phase delay was preferential for bacterial internalization and intracellular proliferation. Using size exclusion chromatography and mass spectroscopy analysis, we identified phenol-soluble modulin alpha (PSMα) peptides as the candidates for this effect. The implication of PSMα in cell cycle alteration was confirmed by testing of synthetic PSMα and by comparison of LACwt with the isogenic mutant LAC∆psm, which lacks the operon encoding PSMα. The delay was associated with a decrease of defensins expression in a G2 phase, suggesting that PSMα-induced G2/M phase transition delay deteriorates antibacterial state of the epithelial surface.Investigation of the response to Escherichia coli and S. aureus showed a higher expression of key cytokines IL-6, IL-8, as well as IL-32 (which is involved in dendritic cell maturation) in E. coli-infected host cells. Comparison of cytokines expression in response to LACwt with isogenic mutants, which lack the operon encoding PSMs, show that PSMs inhibit interleukins production, thus impair the innate and adaptive immune response during S. aureus infection. Therefore we show, that PSMs alter the host cell cycle, resulting in a reduction of defense response of host’ cells, that reveal a newly-identified mechanism for promoting infection