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

Anjuli M Timmer1, John C Timmer, Morgan A Pence

  • 1Department of Pediatrics, Biomedical Sciences Graduate Program, Laboratory of Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA.

The Journal of Biological Chemistry
|November 13, 2008
PubMed

Insights

Group A Streptococcus (GAS) causes invasive infections by inducing rapid macrophage apoptosis via streptolysin O (SLO). This bacterial immune evasion tactic, mediated by SLO, hinders effective host defense against GAS.

Area of Science:

  • Microbiology and Immunology
  • Bacterial Pathogenesis
  • Cellular Biology

Background:

  • Group A Streptococcus (GAS) is a significant human pathogen causing invasive infections.
  • Macrophages are crucial for innate immune defense against GAS.
  • GAS infections can overwhelm host defenses, leading to severe disease.

Purpose of the Study:

  • To investigate the mechanism by which GAS induces apoptosis in phagocytic cells.
  • To identify the specific GAS virulence factor responsible for this apoptosis.
  • To understand the role of SLO-mediated apoptosis in GAS pathogenesis and immune evasion.

Main Methods:

  • Induction of apoptosis in primary and cultured macrophages and neutrophils using GAS.
  • Analysis of GAS virulence factor mutants and heterologous expression of toxins.
  • Ultrastructural studies of mitochondria and assessment of caspase activation and cytochrome c release.
  • In vivo studies using a murine systemic infection model.

Main Results:

  • GAS rapidly induces dose-dependent apoptosis in macrophages and neutrophils.
  • Streptolysin O (SLO) is identified as the necessary and sufficient factor for inducing this apoptosis.
  • SLO-deficient GAS mutants exhibit reduced virulence, increased macrophage cytokine secretion, and less apoptosis in vitro and in vivo.
  • Apoptosis is initiated via the intrinsic pathway, involving mitochondrial damage and caspase activation.

Conclusions:

  • The pore-forming cytolysin SLO directly induces rapid, caspase-dependent macrophage apoptosis.
  • This SLO-mediated apoptosis is a key mechanism for GAS immune evasion.
  • Targeting SLO or its downstream effects could represent a therapeutic strategy against GAS infections.

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