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Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19615-20. doi: 10.1073/pnas.1314400110. Epub 2013 Nov 11.

Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses.

Author information

1
Department of Pathology, Department of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, and Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555.

Abstract

Rickettsiae are responsible for some of the most devastating human infections. A high infectivity and severe illness after inhalation make some rickettsiae bioterrorism threats. We report that deletion of the exchange protein directly activated by cAMP (Epac) gene, Epac1, in mice protects them from an ordinarily lethal dose of rickettsiae. Inhibition of Epac1 suppresses bacterial adhesion and invasion. Most importantly, pharmacological inhibition of Epac1 in vivo using an Epac-specific small-molecule inhibitor, ESI-09, completely recapitulates the Epac1 knockout phenotype. ESI-09 treatment dramatically decreases the morbidity and mortality associated with fatal spotted fever rickettsiosis. Our results demonstrate that Epac1-mediated signaling represents a mechanism for host-pathogen interactions and that Epac1 is a potential target for the prevention and treatment of fatal rickettsioses.

KEYWORDS:

Epac inhibitor; cyclic AMP; prophylaxis; rickettsial infection; therapeutics

PMID:
24218580
PMCID:
PMC3845138
DOI:
10.1073/pnas.1314400110
[Indexed for MEDLINE]
Free PMC Article

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