Intracellular Staphylococcus aureus Perturbs the Host Cell Ca(2+) Homeostasis To Promote Cell Death

The opportunistic human pathogen Staphylococcus aureus causes serious infectious diseases that range from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as an extracellular pathogen, S. aureus is able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction, and the spread of infection. The exact molecular mechanism employed by S. aureus to escape the host cell is still unclear. In this study, we performed a genome-wide small hairpin RNA (shRNA) screen and identified the calcium signaling pathway as being involved in intracellular infection. S. aureus induced a massive cytosolic Ca(2+) increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by a decrease in endoplasmic reticulum Ca(2+) concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca(2+) increase. As a consequence, we observed that the cytoplasmic Ca(2+) rise led to an increase in mitochondrial Ca(2+) concentration, the activation of calpains and caspases, and eventually to cell lysis of S. aureus-infected cells. Our study therefore suggests that intracellular S. aureus disturbs the host cell Ca(2+) homeostasis and induces cytoplasmic Ca(2+) overload, which results in both apoptotic and necrotic cell death in parallel or succession.