RelA signaling in Scgb1a1+ epithelial progenitors mediates alveolar atypia in RSV-induced post viral lung disease

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.