Respiratory syncytial virus hijacks the tumor‐suppressor p53 to enhance its replication in lung epithelial cells

Abstract

Respiratory syncytial virus (RSV) infection is the major cause of childhood lower respiratory illness and has been associated with the induction and exacerbation of asthma. Previously, we reported that RSV infection induced TGF‐β expression that caused cell cycle arrest and subsequently enhanced RSV replication. In the current study, we demonstrate that a downstream target of TGF‐β signaling; P53, is a pivotal transcription factor for RSV replication. Over‐expression of p53 protein by an inducible system (Tet‐off) enhanced RSV replication by 9 folds, whereas, knockdown of p53 using siRNA significantly reduced RSV replication in H1299 and A549 lung epithelial cell lines. Stabilization of p53 with nutlin‐3 enhanced RSV replication by 8 folds in primary human lung epithelial (PHBE) cells. We hypothesized that a plausible mechanism of enhanced RSV replication by p53 was through direct binding of p53 to RSV RNA. A search of RSV genome revealed several putative p53‐responsive elements. To confirm interaction of p53, EMSA analysis was performed which showed a specific shift with one of the p53 response elements. Taken together, we have identified a novel role for p53 in positive regulation of RSV replication. These findings suggest that enhanced p53 expression through lung injury, smoking or air pollution could facilitate a significant increase in RSV replication leading to more severe respiratory pathologies.