The histone demethylase KDM6B fine-tunes the host response to Streptococcus pneumoniae

Connor, M. G. et al. (2021) The histone demethylase KDM6B fine-tunes the host response to Streptococcus pneumoniae. Nature Microbiology, 6(2), pp. 257-269. (doi: 10.1038/s41564-020-00805-8) (PMID:33349663)

Abstract

Streptococcus pneumoniae is a natural colonizer of the human respiratory tract and an opportunistic pathogen. 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 that 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 and requires a histone demethylase KDM6B. We show, molecularly, that the interaction of the 6B strain with epithelial cells leads to chromatin remodelling within the IL-11 promoter in a KDM6B-dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 dimethyl. Remodelling of the IL-11 locus facilitates p65 access to three NF-κB sites that 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 the 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies therefore reveal how a chromatin modifier governs cellular responses during infection.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Rasid, Dr Orhan
• Authors: Connor, M. G., Camarasa, T. M.N., Patey, E., Rasid, O., Barrio, L., Weight, C. M., Miller, D. P., Heyderman, R. S., Lamont, R. J., Enninga, J., and Hamon, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Nature Microbiology
• Publisher: Nature Research
• ISSN: 2058-5276
• ISSN (Online): 2058-5276
• Published Online: 21 December 2020