Pathobiology of Staphyloccocus areus Endocarditis

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The broad goal of this proposed research is to determine the underlying molecular mechanisms required for S. aureus endocarditis vegetations to develop and to improve diagnosis of endocarditis by the use of state-of-the-art molecular imaging techniques. Acute bacterial endocarditis (ABE) is a potentially deadly disease caused by bacterial infection of heart valves. Coagulase-positive S. aureus infections are the leading cause of ABE and have the highest mortality rates, due to the increased incidence of antibiotic- resistance. S. aureus expresses a unique non-proteolytic prothrombin (ProT) activator, staphylocoagulase that mediates recognition of fibrinogen by the active staphylocoagulase-ProT complex resulting in conversion of fibrinogen to fibrin. Fibrin generation is hypothesized to play a critical role in ABE pathology. Here, novel active site-labeled ProT analogs have been developed for use in Fluorescence Molecular Tomography (FMT) and Positron Emission Tomography fused with Computed Tomography (PET-CT) studies to identify S. aureus ABE, noninvasively in a mouse model of the disease. Our hypothesis is that staphylocoagulase activates ProT, while simultaneously localizing the staphylocoagulase-ProT complex to S. aureus vegetations. The specific recognition of vegetations by these agents would facilitate the identification of new adjunctive therapies targeting fibrin generation and its cross-linking by factor Xllla. Molecular imaging, biochemical, and immunology studies are proposed to test our hypotheses: that these ProT analogs specifically recognize ABE;that factor XIII activation stabilizes the fibrin network during ABE;and that new adjunctive therapies can limit vegetation grow in ABE. Specific Aims are: (i) To determine the localization of active site labeled ProT in vivo during S. aureus ABE by the FMT imaging and fluorescence microscopy;(2) To determine the pharmacokinetics of these labeled prothrombin probes and their efficacy in imaging ABE by PET-CT imaging;(3) To determine whether S. aureus-induces activation of FXIII and fibrin cross-linking during ABE;and (4) To characterize the effect of argatroban on the vegetation development during ABE.