Exchange Proteins Directly Activated by cAMP and the Role of these Proteins in Respiratory Syncytial Virus Infection

Abstract

Abstract Respiratory syncytial virus (RSV) is a single-stranded, negative-strand RNA virus belonging to Paramyxoviridae family, and is in the genus Pneumovirus. It was discovered in chimpanzees in 1955 and subsequently confirmed to be a human pathogen shortly after that. RSV is one of the most common viruses to infect young children and high-risk adults worldwide, and the leading cause of inflammation of the lungs (pneumonia) or the lungs’ airways (bronchiolitis) in infants. Due in part to the lack of long-term immunity after infection, making reinfection frequent. There is a single antiviral treatment for RSV currently approved, but its use is limited by questionable efficacy, side effects, and cost, and it is recommended that it be used only for patients at-risk for severe disease, on a case-by-case basis. In this study, we discovered an exchange protein directly activated by cyclic AMP (EPAC) that can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, the treatment of EPAC inhibitor (ESI-09), but not PKA inhibitor (H89), significantly inhibits the RSV replication and pro-inflammatory cytokine/chemokine induction. In addition, RSV-activated transcriptional factors belonging to the NF-κB and IRF families are also suppressed by ESI-09. Through isoform-specific gene knock down, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and viral-induced host responses. Experiments using both EPAC2 knock out and EPAC2 specific inhibitor support such roles of EPAC2. Therefore, EPAC2 could be a promising therapeutic target to regulate RSV replication and associated inflammation.