Rickettsioses represent devastating human infections. Epidemic typhus and Rocky Mountain spotted fever (RMSF) are two of the most lethal infections known to humans. Although rickettsial infections can be controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early, up to 20% of misdiagnosed or untreated and 5% of treated RMSF cases can be fatal. In addition, high infectivity and severe illness after inhalation make rickettsiae potential bioterrorism threats. However, a vaccine is not available for fatal rickettsioses, and novel host mechanism-based prophylactics and therapeutics are urgently needed. cAMP-based cell signaling mediated by intracellular cAMP receptors, Epac1 and 2, are major contributors to the transduction of the effects of cAMP. We have reported that both genetic depletion and pharmacological inactivation of the host Epac1 protected mice from fatal rickettsioses, and in vitro inhibition of Epac1 reduced rickettsial adherence to nonphagocytic cells. The underlying mechanisms remain unknown. We recently found that rickettsiae hijack the annexin A20-S100A10 (AnxA2-p11) complex-mediated host fibrinolytic machinery for their adherence to vascular endothelial cell (EC) surfaces. In addition, our preliminary data show that the deletion of the Epac1 gene or pharmacological inactivation of Epac1 significantly inhibits the associate between AnxA2 and p11, reduces the Anx2-p11 complex on external surfaces of ECs, and attenuates endothelial fibrinolysis. The central hypothesis of this application is that host Epac1 governs rickettsial adhesion to the EC surface in the microenvironment of flowing blood by regulating the formation of the rickettsial binding receptor AnxA2-p11 complex. Our successful collaboration and experience with novel methodologies, as demonstrated in our peer- reviewed joint publications and data from preliminary studies, encourage us to undertake three Specific Aims:
Aim 1 : To test the hypothesis that Epac1 governs rickettsial adhesion by regulating the formation of the rickettsial binding receptor AnxA2-p11 complex in EC through modification of AnxA2.
Aim 2 : To test the hypothesis that inactivation of Epac1 alters AnxA2-p11 complex-mediated functional topographical features of the EC apical surface, thereby affecting rickettsial adhesion.
Aim 3 : To test the hypothesis that genetic and pharmacological inactivation of host Epac1 can attenuate rickettsial adherence to the blood vessel luminal surface under hemodynamic shear stress in vivo. Our major goals are to delineate both biochemical and biomechanical mechanisms underlying the critical role of host Epac1 during a fatal rickettsial infection. Outcomes from this proposed research will represent a major advance in our understanding of rickettsial infection, and in the development of novel prophylactics and potential therapeutics for these dreadful human diseases.

Public Health Relevance

The proposed study focuses on the biochemical and biomechanical mechanisms underlying the recent discovery that Epac1, an exchange protein directly activated by a second messenger known as cAMP, plays a critical role in bacterial adhesion during fatal rickettsioses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Perdue, Samuel S
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University of Texas Med Br Galveston
Schools of Medicine
United States
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Drelich, Aleksandra; Judy, Barbara; He, Xi et al. (2018) Exchange Protein Directly Activated by cAMP Modulates Ebola Virus Uptake into Vascular Endothelial Cells. Viruses 10:
Parnell, Euan; McElroy, Stuart P; Wiejak, Jolanta et al. (2017) Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1. Sci Rep 7:294
Wang, Pingyuan; Liu, Zhiqing; Chen, Haiying et al. (2017) Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets. Bioorg Med Chem Lett 27:1633-1639
Ashraf, Shoaib; Cheng, Jing; Zhao, Xin (2017) Clumping factor A of Staphylococcus aureus interacts with AnnexinA2 on mammary epithelial cells. Sci Rep 7:40608
Schwede, Frank; Bertinetti, Daniela; Langerijs, Carianne N et al. (2015) Structure-guided design of selective Epac1 and Epac2 agonists. PLoS Biol 13:e1002038