Streptococcus pyogenes M1T1 variants activate caspase-1 and induce an inflammatory neutrophil phenotype

Invasive infections due to Group A Streptococcus (GAS) advance rapidly causing tissue degradation and unregulated inflammation. Neutrophils are the primary immune cells that respond to GAS. The neutrophil response to GAS was characterised in response to two M1T1 isolates; 5448 and animal passaged variant 5448AP. Neutrophil co-incubation with 5448AP allowed proliferation of GAS while it also lowered the production of reactive oxygen species by neutrophils when compared with 5448. Infection with both strains invoked neutrophil death, however apoptosis was reduced in response to 5448AP. Both strains induced neutrophil caspase-1 activation and caspase-4 expression in vitro, with caspase-1 activation detected in vivo. Thus, GAS infection of neutrophils corresponds to increased caspase-1 activity and caspase-4 expression, consistent with inflammasome activation and pyroptosis. GAS infections that promote an inflammatory neutrophil phenotype may contribute to increased inflammation yet ineffective bacterial eradication, contributing to the speed and severity of invasive GAS infections.