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

Bin Gong, Thomas Shelite, Fang C. Mei, Tuha Ha, Yaohua Hu, Guang Xu, Qing Chang, Maki Wakamiya, Thomas Ksiazek, Paul J. Boor, Donald Bouyer, Vsevolod Popov, Ju Chen, David Walker, Xiaodong Cheng

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)19615-19620
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number48
DOIs
StatePublished - Nov 26 2013

Fingerprint

Rickettsia
Bacterial Adhesion
Bioterrorism
Host-Pathogen Interactions
Proteins
Inhalation
Fever
Pharmacology
Morbidity
Phenotype
Mortality
Infection
Genes
3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile

Keywords

  • Cyclic AMP
  • Epac inhibitor
  • Prophylaxis
  • Rickettsial infection
  • Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses. / Gong, Bin; Shelite, Thomas; Mei, Fang C.; Ha, Tuha; Hu, Yaohua; Xu, Guang; Chang, Qing; Wakamiya, Maki; Ksiazek, Thomas; Boor, Paul J.; Bouyer, Donald; Popov, Vsevolod; Chen, Ju; Walker, David; Cheng, Xiaodong.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 48, 26.11.2013, p. 19615-19620.

Research output: Contribution to journalArticle

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