Abstract Streptococcus pneumoniae is a natural colonizer of the human upper respiratory tract and an opportunistic pathogen. After colonization, bacteria either remain in the human upper respiratory tract, or may progress to cause pneumococcal disease. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive disease causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 (RelA) and requires a histone demethylase, KDM6B. At the molecular level, we show that interaction of the 6B strain with epithelial cells leads to chromatin remodeling within the IL-11 promoter in a KDM6B dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 di-methyl. Chromatin remodeling of the IL-11 locus facilitates p65 access to three NF-κB sites, which are otherwise inaccessible when stimulated by IL-1β or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B, with GSK-J4 inhibitor, and through exogenous addition of IL-11 that the host responses to 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo . Our studies hereby reveal how a chromatin modifier governs cellular responses during infection.