S. aureus is a major cause of skin and soft tissue infections and we have begun some studies to investigate its interaction with keratinocytes and in the context of infection. We have observed that keratinocytes are capable of activating the caspase-1-depedent pyroptosis pathway and this facilitates invasion across the keratinocyte barrier. Strains that are unable to activate the inflammasome through toxin-mutation for example, are able to persist intracellularly within keratinocytes. We have examined the role of glucose influencing the innate immune system in the context of diabetes and S. aureus infection. Through this work we identified the ClpXP protease as being an important virulence factor. We are examining the role of this protease in multiple infection models as well as its capacity to alter the memory capacity of innate immune cells.