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The opportunistic human pathogenStaphylococcus aureuscauses serious infectious diseases ranging from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as extracellular pathogen,S. aureusis able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction and spread of infection. The exact molecular mechanism employed byS. aureusto escape the host cell is still unclear. In this study, we performed a genome-wide shRNA screen and identified the calcium signaling pathway to be involved in intracellular infection.S. aureusinduced a massive cytosolic Ca2+-increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by decrease in endoplasmic reticulum Ca2+-concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca2+-increase. As a consequence, we observed that the cytoplasmic Ca2+-rise led to increase in mitochondrial Ca2+-concentration, the activation of calpains and caspases and eventually to cell lysis ofS. aureus-infected cells. Our study therefore suggests that intracellularS. aureusdisturbs the host cell Ca2+-homeostasis and induces cytoplasmic Ca2+-overload, which results in both apoptotic and necrotic cell death in parallel or succession.ImportanceDespite being regarded as an extracellular bacterium, the pathogenStaphylococcus aureuscan invade and survive within human cells. The intracellular niche is considered as hide-out from the host immune system and antibiotic treatment and allows bacterial proliferation. Subsequently, the intracellular bacterium induces host cell death, which may facilitate spread of infection and tissue destruction. So far, host cell factors exploited by intracellularS. aureusto promote cell death are only poorly characterized. We performed a genome-wide screen and found the calcium signaling pathway to play a role inS. aureusinvasion and cytotoxicity. The intracellular bacterium induces a cytoplasmic and mitochondrial Ca2+-overload, which results in host cell death. Thus, this study firstly showed how an intracellular bacterium perturbs the host cell Ca2+-homeostasis. |
