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

被引：65

作者：

Gong, Bin ^{[1
]}

Shelite, Thomas ^{[1
]}

Mei, Fang C. ^{[2
]}

Ha, Tuha ^{[1
]}

Hu, Yaohua ^{[2
]}

Xu, Guang ^{[1
]}

Chang, Qing ^{[1
]}

Wakamiya, Maki ^{[3
]}

Ksiazek, Thomas G. ^{[1
]}

Boor, Paul J. ^{[1
]}

Bouyer, Donald H. ^{[1
]}

Popov, Vsevolod L. ^{[1
]}

Chen, Ju ^{[4
]}

Walker, David H. ^{[1
]}

Cheng, Xiaodong ^{[2
]}

机构：

[1] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA

[2] Univ Texas Med Branch, Dept Pharmacol & Toxicol, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA

[3] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA

[4] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 48期

基金：

美国国家卫生研究院;

关键词：

rickettsial infection; cyclic AMP; Epac inhibitor; therapeutics; prophylaxis; MOUNTAIN-SPOTTED-FEVER; CONORII AUTOTRANSPORTER PROTEIN; CCAAT/ENHANCER-BINDING PROTEINS; ENDOTHELIAL BARRIER FUNCTION; EPAC-RAP1 SIGNALING PATHWAY; CYCLIC-AMP; CYTOKINE SIGNALING-3; VASCULAR-PERMEABILITY; MAMMALIAN-CELLS; UNITED-STATES;

D O I：

10.1073/pnas.1314400110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：19615 / 19620

页数：6

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