NF-κB driven inflammation mediates loss of upper airway epithelial tolerance to Streptococcus pneumoniae during influenza co-infection

Streptococcus pneumoniae asymptomatically colonizes the human nasopharynx, where epithelial tolerance maintains mucosal homeostasis. However, influenza A virus (IAV) co-infection transforms this tolerogenic state into an inflammatory environment that promotes bacterial outgrowth and invasion. Here, we identify a TGF-{beta}1 dependent epithelial program that sustains mucosal tolerance during Spn colonization and demonstrate that IAV co-infection disrupts this pathway through IL-17RA-NF-{kappa}B driven inflammation in the nasopharynx. In a murine colonization model, TGF-{beta}1 blockade enhanced pro-inflammatory cytokine production and neutrophil recruitment, resulting in inflammation-driven Spn clearance. IAV co-infection suppressed epithelial TGF-{beta}1 signaling, increased TRAF6/NF-{kappa}B activation, and impaired tight junction integrity, leading to Spn dissemination. Mechanistically, IL-17RA signaling contributed to the hyperactivation of the TRAF6/NF-{kappa}B axis. Pharmacologic inhibition of TRAF6 or NF-{kappa}B restored epithelial barrier function and reduced Spn translocation in a human air-liquid interface nasopharyngeal epithelial model. These findings reveal a conserved epithelial signaling axis through which influenza disrupts mucosal tolerance and promotes Spn invasion, highlighting the canonical TRAF6-NF-{kappa}B pathway as a potential therapeutic target to preserve epithelial integrity and mitigate Spn infection during viral-bacterial co-infection of the upper respiratory tract.