Evasion by Accelerated Macrophage Apoptosis*

Group A Streptococcus (GAS) is a leading human bacterial pathogen capable of producing invasive infections even in pre-viously healthy individuals. As frontline components of host innate defense,macrophages play a key role in control and clear-ance of GAS infections. We find GAS induces rapid, dose-de-pendent 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 fac-tormutants, heterologous expression, andpurified toxin studies identified the pore-forming cytolysin streptolysin O (SLO) as necessary and sufficient for the apoptosis-inducing phenotype. SLO-deficientGASmutants induced lessmacrophage apoptosis in vitro and in vivo, allowedmacrophage cytokine secretion, and were less virulent in a murine systemic infection model. Ultra