Streptococcus pyogenes emm98.1 variants activate inflammatory caspases in human neutrophils

The human pathogen Streptococcus pyogenes (Group A Streptococcus, GAS) is responsible for invasive disease characterized by inflammation and tissue destruction. Inflammatory symptoms of invasive disease may be attributed to the neutrophil response during the early stages of infection. Here, the human neutrophil response to GAS was characterized in vitro using emm98.1 type covS mutant GAS strain NS88.2 (isolated from invasive infection) and avirulent variant NS88.2rep. NS88.2 was shown to resist phagocytic killing and proliferate in the presence of human neutrophils, where neutrophil antimicrobial defence through the production of reactive oxygen species was reduced compared with NS88.2rep. In the presence of NS88.2, neutrophil death was delayed compared with NS88.2rep. Infection with either GAS strain induced expression of inflammatory caspases-1 and -4 in neutrophils, with increased detection of activated inflammatory caspases in response to NS88.2rep compared with NS88.2. NS88.2 infection caused differential expression of cell-surface CD66b, CD16, and CD31, when compared to NS88.2rep. We conclude that the neutrophil response to NS88.2 promotes inflammation and may be a contributing factor to the severity of invasive GAS infections. ABBREVIATIONS: CovRS, control of virulence regulatory system; GAS, Group A Streptococcus; PMN, polymorphonuclear leukocyte.