Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 48, Pages 19615-19620Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314400110
Keywords
rickettsial infection; cyclic AMP; Epac inhibitor; therapeutics; prophylaxis
Categories
Funding
- Center for Biodefense and Emerging Infectious Diseases
- Carmage and Martha Walls Distinguished University Chair in Tropical Diseases
- National Institutes of Health [GM066170]
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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.
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