The role of Exchange Proteins Directly Activated by cAMP in Respiratory Syncytial Virus-induced Pulmonary Pathogenesis

Abstract

Abstract Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in children, the elderly, and immunocompromised patients, representing a huge medical burden globally. However, a specific and effective treatment for RSV infection is not currently available, largely due to poorly understood host-RSV interaction. To facilitate the development of preventive and therapeutic approaches, continuous identification of novel host and viral molecules involved in host responses to RSV and associated pathogenesis is greatly needed. We previously have shown that modulation of cellular EPAC2 protein significantly impacts cellular responses and viral replication in both upper and lower airway epithelial cell models of RSV infection, suggesting EPAC2 could be a promising therapeutic target for RSV infection. In this study, mice deficient in EPAC2 was used to investigate the contribution of EPAC2 to pulmonary responses to RSV infection. EPAC2−/− mice showed less body weight loss and better respiratory function than wildtype mice after RSV infection, suggesting attenuated disease severity. RSV-induced cytokines/chemokines and neutrophil cells in bronchoalveolar lavage fluid (BALF) were also significantly less in EPAC2−/− mice. In addition, histopathology studies revealed less pathogenesis by EPAC2 deletion. Taken together, our data indicate that EPAC2 is a key host molecule contributing to RSV-induced inflammatory responses.