title: Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis.
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.
authors.affiliation: Department of Pediatrics, Biomedical Sciences Graduate Program, Laboratory of Signal Transduction, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Anjuli M
authors.initials: AM
authors.lastname: Timmer
authors.forename: John C
authors.initials: JC
authors.lastname: Timmer
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Pence
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Hsu
authors.forename: Mariam
authors.initials: M
authors.lastname: Ghochani
authors.forename: Terrence G
authors.initials: TG
authors.lastname: Frey
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D001426:Bacterial Proteins / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000472:pathogenicity; D013301:Streptolysins / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001426:Bacterial Proteins; D013301:Streptolysins; C025964:streptolysin O; D045304:Cytochromes c; D020169:Caspases