RT Journal Article
SR Electronic
T1 Pneumococcal carriage requires KDM6B, a histone demethylase, for its unique inflammatory signature
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 757906
DO 10.1101/757906
A1 Michael G. Connor
A1 Emma Patey
A1 Orhan Rasid
A1 Laura Barrio
A1 Daniel P. Miller
A1 Richard J. Lamont
A1 Jost Enninga
A1 Melanie A. Hamon
YR 2019
UL http://biorxiv.org/content/early/2019/09/06/757906.abstract
AB Streptococcus pneumoniae (Sp), a natural colonizer of the human respiratory tract, is a diverse species with over 90 serotypes. Initial pneumococcal colonization of the human nasopharynx induces two distinct host outcomes; asymptomatic carriage or symptomatic invasive pneumococcal disease depending on the serotype and the host response. Epithelial cells are among the first to encounter both carriage and invasive serotype isolates of pneumococcus. However, the cellular processes responsible for the divergent host responses are largely unknown, as is the contribution of epithelial cells to this process. Here, we show a serotype 6B carriage isolate induces a unique inflammatory signature distinct from invasive serotype 4 (Tigr4). This inflammatory signature is characterized by activation of p65 (RelA) and requires a histone demethylase, KDM6B. At the molecular level, we show that interaction of serotype 6B with epithelial cells leads to chromatin remolding within the IL-11 promoter in a KDM6B dependent manner. We show KDM6B specifically demethylates histone H3 lysine 27 di-methyl, and this facilitates p65 access to three NF-κB sites, which are 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 response to carriage or invasive phenotypes can be interchanged. Therefore, we demonstrate that epithelial response to either carriage or invasive serotypes of S. pneumoniae is divergent and is mediated through chromatin remodeling by KDM6B.