Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection

Eun-Jin Choi, Yuping Ren, Yu Chen, Shengxuan Liu, Wenzhe Wu, Junping Ren, Pingyuan Wang, Roberto Garofalo, Jia Zhou, Xiaoyong Bao

Research output: Contribution to journalArticle

Abstract

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 RSV-associated morbidity and mortality.

Original languageEnglish (US)
JournalJournal of Virology
Volume92
Issue number22
DOIs
StatePublished - Nov 15 2018

Fingerprint

Respiratory Syncytial Virus Infections
Respiratory Syncytial Viruses
viruses
virus replication
infection
Virus Replication
Proteins
proteins
inflammation
therapeutics
cAMP-dependent protein kinase
asthma
Gene Knockdown Techniques
cyclic AMP
chemokines
Therapeutics
Bronchiolitis
respiratory tract diseases
pneumonia
morbidity

Keywords

  • EPAC
  • EPAC2
  • inflammation
  • replication
  • replication and immune response
  • RSV

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection. / Choi, Eun-Jin; Ren, Yuping; Chen, Yu; Liu, Shengxuan; Wu, Wenzhe; Ren, Junping; Wang, Pingyuan; Garofalo, Roberto; Zhou, Jia; Bao, Xiaoyong.

In: Journal of Virology, Vol. 92, No. 22, 15.11.2018.

Research output: Contribution to journalArticle

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