The long-term goal of this proposed research is to define the molecular mechanism of vegetation formation during acute bacterial endocarditis (ABE), a potentially deadly human disease caused by bacterial infection of the valves of the heart. The leading cause of deaths from ABE is associated with coagulase-positive Staphylococcus aureus infections which account for 40-50% of neonatal endocarditis and 30-40% of endocarditis in adults between the ages of 16-60 years, with a mortality rate of 25-47%, even with antibiotic therapy. It is our hypothesis that S. aureus bacteremia induces expression of Ly6CHi monocytes leading to increased bacterial attachment to the heart valve surface. S. aureus expresses staphylocoagulase, a bifunctional molecule that activates prothrombin by N-terminal domains and mediates staphylocoagulaseprothrombin complex tethering to the growing vegetations by C-terminal tandem repeats that bind multiple fibrinogen molecules. Novel prothrombin analogs developed in this proposal are hypothesized to localize to the surface of the growing vegetations during ABE and provide new specific probes to monitor S. aureus ABE development, through powerful in vivo molecular imaging methods. Clinical imaging of endocarditis is performed by transesophageal echocardiogram, which is often difficult to interpret due to poor images and variable bacterial attachment. It is our contention that the use of these novel-imaging agents will be directly translatable to the clinical environment and ultimately, led to improved patient outcomes. The hypotheses proposed above will be tested by the following specific aims:
Aim 1. To characterize monocyte response to S. aureus-mediate ABE and to define the role of these cells in vegetation formation, Aim 2. To determine the localization of active site labeled prothrombin in vivo during S. aureus endocarditis, and Aim 3. To characterize the effect of argatroban on the development of fibrin-bacteria-platelet vegetations during ABE. ? ? ?
| Laha, Malabika; Panizzi, Peter; Nahrendorf, Matthias et al. (2011) Engineering streptokinase for generation of active site-labeled plasminogen analogs. Anal Biochem 415:105-15 |
| Panizzi, Peter; Nahrendorf, Matthias; Figueiredo, Jose-Luiz et al. (2011) In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation. Nat Med 17:1142-6 |
