Abstract

Streptococcus pneumoniae colonises the nasopharynx asymptomatically yet causes life-threatening invasive disease. How it navigates early epithelial immune surveillance to cause disease remains unclear. Conventional innate immune models predict coordinated, population-wide epithelial responses to bacterial infection. Using single-cell RNA sequencing, RNA fluorescence in situ hybridization and in vivo mouse and zebrafish models, pneumococcal infection is instead shown to activate innate immune genes including chemokine, NF-{kappa}B regulatory, and prostaglandin pathway genes, in only 1-4% of lung epithelial cells. This restriction is seemingly pneumococcal-specific as Escherichia coli triggers responses in over 40% of the same cells. Strikingly, nasopharyngeal epithelial cells show complete immune silence to pneumococci while responding robustly to E. coli and Staphylococcus aureus, suggesting niche-specific immune evasion. Additionally, pharmacological inhibition of COX-2 significantly increased mortality in a zebrafish meningitis model, identifying prostaglandin signalling as a protective host response during invasive disease. Competence-associated surface remodelling contributes modestly and incrementally to immune restriction, while the predominant dampening is competence-independent. These findings challenge canonical epithelial immunity models against bacterial infection and provide a cellular framework for understanding pneumococcal commensalism and pathogenesis.