Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis

J Biol Chem. 2009 Jan 9;284(2):862-71. doi: 10.1074/jbc.M804632200. Epub 2008 Nov 11.


Group 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / immunology*
  • Bacterial Proteins / pharmacology
  • Caspases / metabolism
  • Cell Line
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Female
  • Humans
  • Macrophages / cytology*
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / immunology*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / ultrastructure
  • Streptococcus pyogenes / immunology*
  • Streptococcus pyogenes / pathogenicity
  • Streptolysins / pharmacology*
  • Time Factors


  • Bacterial Proteins
  • Streptolysins
  • streptolysin O
  • Cytochromes c
  • Caspases