GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE291nnn/GSE291797/primaryOK200TranscriptomicsMus musculus Human respiratory syncytial virus A strain LongExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE291797GEOGSEfalseRelA signaling in Scgb1a1+ epithelial progenitors mediates alveolar atypia in RSV-induced post viral lung diseaseEarly life respiratory virus infections play an important role in shaping structural and immunological responses of the lung, leading to chronic airway disease Respiratory syncytial virus (RSV), a member of genus Orthopneumovirus, is an etiological agent in infant lower respiratory tract infections (LRTIs) producing substantial global morbidity. The mechanisms underlying how transient RSV infection produces long-term structural changes are unexplored. Although it is known that airway repair is mediated by expansion of parenchymal epithelial progenitors within discrete mesenchymal niches, the nature of these cells and how they are activated by viral infection are unknown. Herein, we explore the impact of RSV infection on trophic mesenchymal-basal epithelial interactions and the regenerative role of innate NFB/RelA signaling by its conditional knockout (CKO) in secretoglobin (Scgb1a1)-derived progenitors. We discovered that RSV-induced post viral lung disease (PVLD) induces expansion of parenchymal airspace and replacement of small bronchiolar and alveolar epithelium by tumor protein 63 (Trp63), Aquaporin-3 (Aqp3) and Integrin 4 (Itg4)-expressing cells. Single-cell RNA sequencing identifies populations of atypical alveolar type (AT)2 cells expressing both AT2 and AT1 markers. Mechanistically, we find this atypical progenitor expansion is prevented by RelA CKO in the Scgb1a1 lineage. A probabilistic analysis of the mesenchymal-epithelial cell-cell signaling network shows RSV induces an extensive network of epithelial-mesenchymal signaling through inflammatory platelet activated receptor (PAR), IL1/IL4 and stem-cell signaling by angiopoietin like (ANGPTL)-4 pathway. Interestingly, ANGPTL4 is normalized after Scgb1a1-directed RelA CKO. These data indicate RSV-PVLD is mediated, at least in part, by dysregulated mesenchymal-epithelial trophic signaling downstream of RelA activation in Scgb1a1-derived epithelial progenitors.2026/04/01GSE291797GSM8842525GSM8842514GSM8842524GSM8842516GSM8842515GSM8842518GSM8842517GSM8842519GSM8842521GSM8842520GSM8842523GSM88425223566434290291797Mus musculus Human respiratory syncytial virus A strain Long[41898720]