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Fluorescent Probe Finds S. Aureus Inside Infected Hearts

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BOSTON, Aug. 23, 2011 — A novel imaging probe may make it possible to diagnose accurately a dangerous infection of the heart valves. Investigators at Massachusetts General Hospital (MGH) found that the presence of Staphylococcus aureus-associated endocarditis in a mouse model can be unveiled by PET imaging using a radiolabeled version of a protein involved in a process that usually conceals infecting bacteria from the immune system.

“Our probe was able to sense whether S. aureus was present in abnormal growths that hinder the normal function of heart valves,” said Matthias Nahrendorf of the MGH Center for Systems Biology. “It has been very difficult to identify the bacteria involved in endocarditis, but a precise diagnosis is important to steering well-adjusted antibiotic therapy.”

PET-CT image of S. aureus endocarditis. Images A and B show a molecular model of how the PET reporter (yellow structure with colored spheres) binds to the target, the bacterial enzyme staphylocoagulase (violet). Image B is rotated 90° relative to image A. CT (images C and D) and PET-CT (images E and F) show the location of the radiolabeled prothrombin in vegetations (arrowhead) around the aortic valve (asterisk) of a mouse heart. Images G-I show the location of the PET agent in aortas of mice with (G-H) and without (I-J) S. aureus endocarditis. (Image: Massachusetts General Hospital)

An infection of the tissue lining the heart valves, endocarditis is characterized by growths called vegetations that are made up of clotting components such as platelets and fibrin along with infecting microorganisms. Endocarditis caused by S. aureus is the most dangerous, with a mortality rate of from 25 to almost 50 percent, but diagnosis can be difficult because symptoms, such as fever and heart murmur, are vague, and blood tests may not detect the involved bacteria. Without appropriate antibiotic therapy, S. aureus endocarditis can progress rapidly, damaging or destroying heart valves.

S. aureus bacteria initiate the growth of vegetations by secreting staphylocoagulase, an enzyme that sets off the clotting cascade. This process involves prothrombin, a protein that is part of a pathway leading to the deposition of fibrin, a primary component of blood clots. The clotting process enlarges the vegetation, anchors it to the heart valve and serves to conceal the bacteria from immune cells in the bloodstream.

To develop an imaging-based approach to diagnosing S. aureus endocarditis, the MGH team first investigated the molecular mechanism by which staphylocoagulase sets off the clotting cascade, finding that one staphylocoagulase molecule interacts with at least four molecules of fibrin or its predecessor molecule fibrinogen in a complex that binds to a growing vegetation. Because prothrombin is an essential intermediary in the staphylocoagulase/fibrin interaction, the researchers investigated whether labeled versions of prothrombin could accurately detect S. aureus endocarditis in mice.

After initial experiments confirmed that an optical imaging technology called FMT-CT (fluorescence molecular tomography/computed tomography) could detect a fluorescence-labeled version of prothrombin deposited into S. aureus-induced vegetations, the researchers showed that a radiolabeled version of prothrombin enabled the detection of the vegetations with combined PET-CT (positron emission tomography/ computed tomography) imaging, an approach that could be used in human patients after additional development and FDA approval.

“An approach like this could help clinicians detect the presence of endocarditis, determine its severity and whether it is caused by S. aureus, and track the effectiveness of antibiotics or other treatments,” Nahrendorf said. “We are working to improve the PET reporter probe with streamlined chemistry and a more mainstream PET isotope to make it a better candidate for eventual testing in patients.”

The group reported its efforts in a recent issue of Nature Medicine.

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Aug 2011
AmericasbacteriaBasic ScienceBiophotonicscomputed tomographyendocarditisfibrinfibrinogenfluorescence molecular tomographyFMT-CTheart valvesimagingimaging probesMassachusettsMassachusetts General HospitalMatthias NahrendorfMGH Center for Systems BiologyPET imagingPET-CTpositron emission tomographyprothrombinResearch & TechnologystaphylocoagulaseStaphylococcus aureusvegetations

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