Epithelial micro-invasion byStreptococcus pneumoniaeinduces epithelial-derived innate immunity during colonisation at the human mucosal surface

ABSTRACT Control of Streptococcus pneumoniae colonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Using an Experimental Human Pneumococcal Carriage Model (EHPC), we show that S. pneumoniae colonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium in vitro shaped the host transcriptomic response. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling/ regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. These results show that rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances the inflammatory/ innate immune response associated with clearance.