{"doi":"10.1101/2025.10.25.684585","title":"NF-κB driven inflammation mediates loss of upper airway epithelial tolerance to <i>Streptococcus pneumoniae</i> during influenza co-infection","abstract":"Abstract 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-β1 dependent epithelial program that sustains mucosal tolerance during Spn colonization and demonstrate that IAV co-infection disrupts this pathway through IL-17RA-NF-κB driven inflammation in the nasopharynx. In a murine colonization model, TGF-β1 blockade enhanced pro-inflammatory cytokine production and neutrophil recruitment, resulting in inflammation-driven Spn clearance. IAV co-infection suppressed epithelial TGF-β1 signaling, increased TRAF6/NF-κB activation, and impaired tight junction integrity, leading to Spn dissemination. Mechanistically, IL-17RA signaling contributed to the hyperactivation of the TRAF6/NF-κB axis. Pharmacologic inhibition of TRAF6 or NF-κB 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-κB pathway as a potential therapeutic target to preserve epithelial integrity and mitigate Spn infection during viral-bacterial co-infection of the upper respiratory tract.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559376,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":282912,"name":"Zhihan Wang","orcid":"0000-0002-3617-477X","position":1,"is_corresponding":false},{"id":282916,"name":"Kai Guo","orcid":"0000-0002-4651-781X","position":2,"is_corresponding":false},{"id":1460588,"name":"Syed Hasan","orcid":"0000-0002-5623-1209","position":3,"is_corresponding":false},{"id":465946,"name":"Taylor Schmit","orcid":"0000-0002-7637-1110","position":4,"is_corresponding":false},{"id":1461192,"name":"Jamanah Ahsan","orcid":null,"position":5,"is_corresponding":false},{"id":322588,"name":"Ramkumar Mathur","orcid":"0000-0002-9317-2631","position":6,"is_corresponding":false},{"id":350442,"name":"Junguk Hur","orcid":"0000-0002-0736-2149","position":7,"is_corresponding":false},{"id":718883,"name":"Nadeem Khan","orcid":"0000-0003-3511-6356","position":8,"is_corresponding":false},{"id":976767,"name":"Zahrasadat Navaeiseddighi","orcid":"0000-0002-4300-9748","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41279507","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}