Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses.
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.
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.
Bin
B
Gong
Thomas
T
Shelite
Fang C
FC
Mei
Tuha
T
Ha
Yaohua
Y
Hu
Guang
G
Xu
Qing
Q
Chang
Maki
M
Wakamiya
Thomas G
TG
Ksiazek
Paul J
PJ
Boor
Donald H
DH
Bouyer
Vsevolod L
VL
Popov
Ju
J
Chen
David H
DH
Walker
Xiaodong
X
Cheng
D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects* / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012282:Rickettsia Infections / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007555:Isoxazoles
Epac inhibitor; cyclic AMP; prophylaxis; rickettsial infection; therapeutics