Synergistic Action of Staphylococcus aureus α-Toxin on Platelets and Myeloid Lineage Cells Contributes to Lethal Sepsis

Multi-organ failure contributes to mortality in bacterial sepsis. Platelet and immune cell activation contribute to organ injury during sepsis, but the mechanisms by which bacterial virulence factors initiate these responses remain poorly defined. We demonstrate that during lethal sepsis, Staphylococcus aureus α-toxin simultaneously alters platelet activation and promotes neutrophil inflammatory signaling through interactions with its cellular receptor ADAM10. Platelet intoxication prevents endothelial barrier repair and facilitates formation of injurious platelet-neutrophil aggregates, contributing to lung and liver injury that is mitigated by ADAM10 deletion on platelets and myeloid lineage cells. While platelet- or myeloid-specific ADAM10 knockout does not alter sepsis mortality, double-knockout animals are highly protected. These results define a pathway by which a single bacterial toxin utilizes a widely expressed receptor to coordinate progressive, multi-organ disease in lethal sepsis. As an expression-enhancing ADAM10 polymorphism confers susceptibility to severe human sepsis, these studies highlight the importance of understanding molecular host-microbe interactions.