A novel imaging probe developed by Massachusetts General Hospital (MGH) investigators may make it possible to diagnose accurately a dangerous infection of the heart valves.
In their Nature Medicine report, which is receiving advance online publication, the team from the MGH Center for Systems Biology describes how the presence of Staphylococcus aureus-associated endocarditis in a mouse model was revealed by PET imaging with 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," says Matthias Nahrendorf, MD, PhD, of the MGH Center for Systems Biology, a co-lead author of the study. "It has been very difficult to identify the bacteria involved in endocarditis, but a precise diagnosis is important to steering well-adjusted antibiotic therapy."
An infection of the tissue lining the heart valves, endocarditis is characterized by growths called vegetations 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 since 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 a protein called prothrombin, which 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. Since 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 could detect a fluorescence-labeled version of prothombin deposited into S. aureus-induced vegetations, the researchers showed that a radiolabeled version of prothombin enabled the detection of S. aureus vegetations with combined PET-CT 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," says Nahrendorf, also a co-corresponding author of the Nature Medicine article and an assistant professor of Radiology at Harvard Medical School. "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."
Peter Panizzi, PhD, of the Harrison School of Pharmacy at Auburn University is co-lead author of the Nature Medicine paper; and Ralph Weissleder, MD, PhD, director of the MGH Center for Systems Biology is senior and co-corresponding author. Additional co-authors are Jose-Luiz Figueiredo, Brett Marinelli, Yoshi Iwamoto, Edmund Keliher, Peter Waterman, Florian Leuschner, Elena Aikawa, Filip Swirski and Mikael Pittet, MGH Center for Systems Biology; Jennifer Panizzi, MGH Nephrology; Ashoka Maddur, Heather Kroh and Paul Bock, Vanderbilt University School of Medicine; Tilman Hackeng, University of Maastricht, The Netherlands; Pablo Fuentes-Prior, Hospital de la Santa Creu, Barcelona, Spain; and Olaf Schneewind, University of Chicago. The study was supported by the U.S. National Institutes of Health.
Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital (www.massgeneral.org) is the original and largest teaching hospital of Harvard Medical School. MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $700 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
Sue McGreevey | EurekAlert!
Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University
3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences