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ABSTRACTThe capacity for intracellular survival within phagocytes is likely a critical factor facilitating the dissemination of Staphylococcus aureusin the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and, to a lesser extent, macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone marrow-derived DCs (BMDCs), we demonstrate for the first time that DCs can effectively kill S. aureusbut that certain strains of S. aureushave the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs, and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3-methyladenine restored the bactericidal effects of BMDCs. Using an in vivomodel of systemic infection, we demonstrated that the ability of S. aureusstrains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together, our data suggest that strains of S. aureusexhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes, the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination.

ABSTRACTRecent work has identified T cells and the cytokines they produce as important correlates of immune protection during Staphylococcus aureusinfections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for ?dT cells in controlling S. aureussurgical site infection (SSI). ?dT cells are recruited to the wound site following S. aureuschallenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-?dT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor-deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during S. aureusSSI. However, we demonstrate a strain-dependent requirement for ?dT cells in this process due to the differential abilities of individual strains to activate IL-1ß production. IL-1ß processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control S. aureusSSI due to reduced production of IL-17 by ?dT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during S. aureusinfection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during S. aureusSSI, the relative contribution of ?dT cells to these protective effects may be strain dependent.