Compared to wild-type, infection of Detroit 562 epithelial cells by the Δfhs/piaA strain, but not the ΔproABC/piaA strain, was less proinflammatory, induced less caspase 8 production, and was associated with increased pneumococcal hydrogen peroxide and reduced pneumolysin secretion.<h4>Conclusions</h4>These findings suggest that differences in microinvasion and epithelial responses were driven by the differential expression of multiple bacterial virulence and metabolic pathways. Here, CASP8 is linked to infection.