Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular,but Not Intracellular

Staphylococcus aureus infections are a growing health burden worldwide,and paramount to this bacterium’s pathogenesis is the production of virulence factors,including pore-forming leukotoxins. leukocidin a/b (lukab) is a recently discovered toxin that kills primary human phagocytes,though the underlying mechanism of cell death is not understood. we demonstrate here that lukab is a major contributor to the death of human monocytes. using a variety of in vitro and ex vivo intoxication and infection models,we found that lukab activates caspase 1,promotes il-1β secretion and induces necrosis in human monocytes. using thp1 cells as a model for human monocytes,we found that the inflammasome components nlrp3 and asc are required for lukab-mediated il-1β secretion and necrotic cell death. s. aureus was shown to kill human monocytes in a lukab dependent manner under both extracellular and intracellular ex vivo infection models. although lukab-mediated killing of thp1 monocytes from extracellular s. aureus requires asc,nlrp3 and the lukab-receptor cd11b,lukab-mediated killing from phagocytosed s. aureus is independent of asc or nlrp3,but dependent on cd11b. altogether,this study provides insight into the nature of lukab-mediated killing of human monocytes. the discovery that s. aureus lukab provokes differential host responses in a manner dependent on the cellular contact site is critical for the development of anti-infective/anti-inflammatory therapies that target the nlrp3 inflammasome. © 2015 melehani et al.