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

ABSTRACTControl ofStreptococcus pneumoniaecolonisation 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 thatS. pneumoniaecolonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epitheliumin vitroshaped the host transcriptomic response. Using epithelial modules from a human epithelial cell model that recapitulates ourin vivofindings, 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.