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. M1T1 GAS isolate 5448 and animal passaged variant 5448AP, containing a covS mutation, were assessed for their influence on neutrophils. 5448AP proliferated during neutrophil co-incubation and induced lower neutrophil reactive oxygen species production 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 in vitro, and elicited IL-1β and TNF-α release from neutrophils. GAS infection altered the cell-surface expression of CD16 and CD31 on neutrophils. In vivo mouse studies confirmed activation of caspase-1 in neutrophils, while 5448AP infection increased circulating IL-1β. GAS infections that promote an inflammatory neutrophil phenotype may contribute to increased inflammation yet ineffective bacterial eradication, contributing to the severity of invasive GAS infections.