Streptolysin O Promotes Group A Streptococcus Immune Evasion by Accelerated Macrophage Apoptosis

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-d...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-01, Vol.284 (2), p.862-871
Main Authors: Timmer, Anjuli M., Timmer, John C., Pence, Morgan A., Hsu, Li-Chung, Ghochani, Mariam, Frey, Terrence G., Karin, Michael, Salvesen, Guy S., Nizet, Victor
Format: Article
Language:English
Subjects:
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
Mechanisms of Signal Transduction
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M804632200