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 G. Ksiazek; Paul J. Boor; Donald H. Bouyer; Vsevolod L. Popov; Ju Chen; David H. Walker; Xiaodong Cheng

doi:10.1073/pnas.1314400110

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 G. Ksiazek, Paul J. Boor, Donald H. Bouyer, Vsevolod L. Popov, Ju Chen, David H. Walker, Xiaodong Cheng

Pathology

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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 language	English (US)
Pages (from-to)	19615-19620
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	48
DOIs	https://doi.org/10.1073/pnas.1314400110
State	Published - Nov 26 2013

Keywords

Cyclic AMP
Epac inhibitor
Prophylaxis
Rickettsial infection
Therapeutics

ASJC Scopus subject areas

General

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10.1073/pnas.1314400110

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Gong, B., Shelite, T., Mei, F. C., Ha, T., Hu, Y., Xu, G., Chang, Q., Wakamiya, M., Ksiazek, T. G., Boor, P. J., Bouyer, D. H., Popov, V. L., Chen, J., Walker, D. H., & Cheng, X. (2013). Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses. Proceedings of the National Academy of Sciences of the United States of America, 110(48), 19615-19620. https://doi.org/10.1073/pnas.1314400110

Gong, B, Shelite, T, Mei, FC, Ha, T, Hu, Y, Xu, G, Chang, Q, Wakamiya, M, Ksiazek, TG, Boor, PJ, Bouyer, DH , Popov, VL, Chen, J, Walker, DH & Cheng, X 2013, 'Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 48, pp. 19615-19620. https://doi.org/10.1073/pnas.1314400110

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AU - Xu, Guang

AU - Chang, Qing

AU - Wakamiya, Maki

AU - Ksiazek, Thomas G.

AU - Boor, Paul J.

AU - Bouyer, Donald H.

AU - Popov, Vsevolod L.

AU - Chen, Ju

AU - Walker, David H.

AU - Cheng, Xiaodong

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

Abstract

Keywords

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