Timmer, Anjuli MAnjuli MTimmerTimmer, John CJohn CTimmerPence, Morgan AMorgan APenceLI-CHUNG HSUGhochani, MariamMariamGhochaniFrey, Terrence GTerrence GFreyKarin, MichaelMichaelKarinSalvesen, Guy SGuy SSalvesenNizet, VictorVictorNizet2024-04-262024-04-262009-01-090021-9258https://scholars.lib.ntu.edu.tw/handle/123456789/642063Group A Streptococcus (GAS) is a leading human bacterial pathogen capable of producing invasive infections even in previously healthy individuals. As frontline components of host innate defense, macrophages play a key role in control and clearance of GAS infections. We find GAS induces rapid, dose-dependent apoptosis of primary and cultured macrophages and neutrophils. The cell death pathway involves apoptotic caspases, is partly dependent on caspase-1, and requires GAS internalization by the phagocyte. Analysis of GAS virulence factor mutants, heterologous expression, and purified toxin studies identified the pore-forming cytolysin streptolysin O (SLO) as necessary and sufficient for the apoptosis-inducing phenotype. SLO-deficient GAS mutants induced less macrophage apoptosis in vitro and in vivo, allowed macrophage cytokine secretion, and were less virulent in a murine systemic infection model. Ultrastructural evidence of mitochondrial membrane remodeling, coupled with loss of mitochondrial depolarization and cytochrome c release, suggests a direct attack of the toxin initiates the intrinsic apoptosis pathway. A general caspase inhibitor blocked SLO-induced apoptosis and enhanced macrophage killing of GAS. We conclude that accelerated, caspase-dependent macrophage apoptosis induced by the pore-forming cytolysin SLO contributes to GAS immune evasion and virulence.enjournal article10.1074/jbc.M804632200190014202-s2.0-59449086954https://scholars.lib.ntu.edu.tw/handle/123456789/346452http://www.scopus.com/inward/record.url?eid=2-s2.0-59449086954&partnerID=MN8TOARS