Exchange Protein Directly Activated by cAMP 2 Enhances Respiratory Syncytial Virus-Induced Pulmonary Disease in Mice

Front Immunol. 2021 Oct 18:12:757758. doi: 10.3389/fimmu.2021.757758. eCollection 2021.

Abstract

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children. It is also a significant contributor to upper respiratory tract infections, therefore, a major cause for visits to the pediatrician. High morbidity and mortality are associated with high-risk populations including premature infants, the elderly, and the immunocompromised. However, no effective and specific treatment is available. Recently, we discovered that an exchange protein directly activated by cyclic AMP 2 (EPAC2) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, EPAC2 promotes RSV replication and pro-inflammatory cytokine/chemokine induction. However, the overall role of EPAC2 in the pulmonary responses to RSV has not been investigated. Herein, we found that EPAC2-deficient mice (KO) or mice treated with an EPAC2-specific inhibitor showed a significant decrease in body weight loss, airway hyperresponsiveness, and pulmonary inflammation, compared with wild-type (WT) or vehicle-treated mice. Overall, this study demonstrates the critical contribution of the EPAC2-mediated pathway to airway diseases in experimental RSV infection, suggesting the possibility to target EPAC2 as a promising treatment modality for RSV.

Keywords: EPAC2; RSV; immune response; inflammation; pulmonary disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Obstruction / etiology
  • Animals
  • Cyclic AMP / physiology
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Granulocyte Colony-Stimulating Factor / biosynthesis
  • Granulocyte Colony-Stimulating Factor / genetics
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / deficiency
  • Guanine Nucleotide Exchange Factors / physiology*
  • Inflammation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Respiratory Hypersensitivity / etiology
  • Respiratory Syncytial Virus Infections / complications
  • Respiratory Syncytial Virus Infections / drug therapy
  • Respiratory Syncytial Virus Infections / physiopathology*
  • Respiratory Syncytial Viruses / physiology
  • Specific Pathogen-Free Organisms
  • Virus Replication
  • Weight Loss

Substances

  • Cytokines
  • Guanine Nucleotide Exchange Factors
  • Rapgef4 protein, mouse
  • Granulocyte Colony-Stimulating Factor
  • Cyclic AMP