PIWIL4 regulates gene expression and piRNA levels in RSV-infected airway epithelial cells.

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infection in young children, the elderly, and immunocompromised hosts, and no RSV vaccine or therapy exists for infants, beyond prophylaxis. PIWI-interacting RNAs (piRNAs), small non-coding RNAs acting through P element-induced wimpy testis (Piwi) proteins, remain largely unexplored. We characterized PIWIL4 expressions and function during RSV infection or poly(I:C) stimulation, a proxy of viral infection. PIWIL4 was expressed in primary and immortalized small airway epithelial cells following RSV infection. While PIWIL4 knockdown did not affect RSV replication, it decreased cytokine and growth factor secretion, altered gene and piRNA expression, and modulated pathways involved in cytokine production, metabolism, and airway remodeling. Limited overlap between piRNA targets and transcriptomic changes suggests PIWIL4 regulates airway epithelial cell responses partly independently of piRNAs. Our study positions PIWIL4 as a key regulator of airway epithelial cell responses to viral infections.