Invasive infections due to Streptococcus pyogenes (Group A Streptococcus, GAS) cause tissue degradation and sepsis as a result of dysregulated host immune reactions. Polymorphonuclear leukocytes (PMNs) are the primary responding innate immune cells to infection. PMN dysfunction due to changes in activation, regulated cell-death pathway and clearance is associated with invasive disease. GAS responsible for invasive disease frequently acquire mutations in the two-component control of virulence regulator system sensor protein (covS), increasing GAS resistance to PMN killing and promoting bacterial dissemination. We have undertaken an investigation of the PMN response to covS mutant GAS. We show, for the first time, that GAS promotes activation of caspase-1 in PMNs, suggesting inflammasome activation in response to both wildtype and covS mutant GAS. In addition, PMNs exposed to covS mutant GAS show evidence of delayed cell-death, decreased caspase-3 activation, and retention of CD16 and CD31 expression, compared to PMNs infected with wildtype GAS. These data support a hypothesis that reduced phagocytosis of covS mutant GAS may contribute to delayed PMN clearance during infection. Furthermore, LEGENDplex cytometric bead assay analysis reveals PMNs infected with covS GAS release increased IL-1β but reduced TNF-α, which could further contribute to inflammation. We hypothesise that infection of PMNs with covS mutant GAS results in decreased PMN function, delayed PMN cell death, and a reduction in PMN apoptosis, thereby promoting an inflammatory phenotype and allowing bacterial proliferation. Ineffective PMN function during the early stages of invasive GAS infection may be a contributing factor to the development of sepsis.