TY - JOUR
T1 - Exchange proteins directly activated by cAMP and their roles in respiratory syncytial virus infection
AU - Choi, Eun-Jin
AU - Ren, Yuping
AU - Chen, Yu
AU - Liu, Shengxuan
AU - Wu, Wenzhe
AU - Ren, Junping
AU - Wang, Pingyuan
AU - Garofalo, Roberto P.
AU - Zhou, Jia
AU - Bao, Xiaoyong
N1 - Funding Information:
This work was supported by grants from the National Institute of Allergy and Infectious Diseases, NIH (1R01AI107033-01 and R21AI113771-01A1), and a Flight Attendant Medical Research Institute Clinical Innovator Award to X.B. We thank Animesh Chandra for assistance with manuscript editing and Cynthia Tribble for graphics preparation. A. Chandra is supported by the UTMB CTSA, funded by NCATS grant UL1TR001439. We thank Kimberly Palkowetz for technical assistance. We have no conflicts of interest to report.
Publisher Copyright:
© 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children and high-risk adults. However, a specific treatment for this viral infection is not currently available. In this study, we discovered that an exchange protein directly activated by cyclic AMP (EPAC) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, treatment with EPAC inhibitor (ESI-09), but not protein kinase A inhibitor (H89), significantly inhibits RSV replication and proinflammatory 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 knockdown, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. Experiments using both EPAC2 knockout and EPAC2-specific inhibitor support such roles of EPAC2. Therefore, EPAC2 is a promising therapeutic target to regulate RSV replication and associated inflammation. IMPORTANCE RSV is a serious public health problem, as it is associated with bronchiolitis, pneumonia, and asthma exacerbations. Currently no effective treatment or vaccine is available, and many molecular mechanisms regarding RSV-induced lung disease are still significantly unknown. This project aims to elucidate an important and novel function of a protein, called EPAC2, in RSV replication and innate inflammatory responses. Our results should provide an important insight into the development of new pharmacologic strategies against RSV infection, thereby reducing RSVassociated morbidity and mortality.
AB - Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children and high-risk adults. However, a specific treatment for this viral infection is not currently available. In this study, we discovered that an exchange protein directly activated by cyclic AMP (EPAC) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, treatment with EPAC inhibitor (ESI-09), but not protein kinase A inhibitor (H89), significantly inhibits RSV replication and proinflammatory 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 knockdown, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. Experiments using both EPAC2 knockout and EPAC2-specific inhibitor support such roles of EPAC2. Therefore, EPAC2 is a promising therapeutic target to regulate RSV replication and associated inflammation. IMPORTANCE RSV is a serious public health problem, as it is associated with bronchiolitis, pneumonia, and asthma exacerbations. Currently no effective treatment or vaccine is available, and many molecular mechanisms regarding RSV-induced lung disease are still significantly unknown. This project aims to elucidate an important and novel function of a protein, called EPAC2, in RSV replication and innate inflammatory responses. Our results should provide an important insight into the development of new pharmacologic strategies against RSV infection, thereby reducing RSVassociated morbidity and mortality.
KW - EPAC
KW - EPAC2
KW - Inflammation
KW - RSV
KW - Replication
KW - Replication and immune response
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U2 - 10.1128/JVI.01200-18
DO - 10.1128/JVI.01200-18
M3 - Article
C2 - 30185593
AN - SCOPUS:85055613469
SN - 0022-538X
VL - 92
JO - Journal of virology
JF - Journal of virology
IS - 22
M1 - e01200-18
ER -