Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis
Journal
The Journal of Biological Chemistry
Journal Volume
284
Journal Issue
2
Pages
862-871
Date Issued
2009-01-09
Author(s)
Timmer, Anjuli M
Timmer, John C
Pence, Morgan A
Ghochani, Mariam
Frey, Terrence G
Karin, Michael
Salvesen, Guy S
Nizet, Victor
Abstract
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.
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Type
journal article