Clinical management of acute endocarditis, a frequent and deadly infection of the heart valves (mortality of up to 47%), remains highly challenging and often unsuccessful1,2. The most common pathogen in acute endocarditis is Staphylococcus aureus, followed by streptococcus species2,3. Unmet clinical needs include: (i) reliable diagnosis or exclusion of endocarditis, (ii) specific identification of the pathogen informing selection of antibiotics, and (iii) acquisition of quantitative data to guide surgical intervention. Here we aim to develop a clinically viable, novel method for pathogen-specific imaging of Staphylococcus aureus endocarditis. Our strategy is based on the ultrahigh affinity (17pM)5 of the virulence factor staphylocoagulase, which is secreted by the bacteria, to prothrombin (ProT) and the use of this interaction to develop specific imaging probes6. Staphylocoagulase's NH2-terminal D1 and D2-domains bind to thrombin (or the ProT imaging platform), while the COOH-terminal repeats region binds to fibrinogen at the same time. Therefore, staphylocoagulase firmly anchors the imaging probe in endocarditic vegetations. Our preliminary data show that harnessing the high affinity between ProT and staphylocoagulase for engineering imaging agents is feasible (Nature Med. 2011)6. We used prothrombin's activation pocket that tightly binds to staphylocoagulase by a mechanism dubbed "molecular sexuality" (Bode and Huber 1976)7 as an affinity ligand. Labeling ProT's serine protease active site with a fluorochrome allowed us to detect and monitor S. aureus endocarditis in a mouse model with optical imaging6. Furthermore, we synthesized a PET reporter for S. aureus (64Cu-iProT) and found that sensitive PET imaging of staphylocoagulase is also feasible. The studies proposed in the first aim are based on this already-established imaging agent but will also pursue development of alternative imaging agents targeted to other bacterial strains.
The second aim describes developing 18F compounds with optimized pharmacokinetics using click chemistry, which we recently adopted for facile synthesis of PET agents8,9. Two lead compounds will be tested in a G?ttingen minipig model of endocarditis. We will employ these probes to image murine endocarditis by hybrid ECG- triggered PET/CT and PET/MRI, thereby combining a sensitive molecular modality (PET) with a leading modality for assessing left ventricular function which can also detect valvular insufficiency (MRI). Agent development will focus on clinical feasibility to address the aforementioned urgent medical needs, with the ultimate goal of using PET/MRI detection of bacteria in valve lesions for the diagnosis of acute endocarditis in patients.

Public Health Relevance

We propose to develop a clinically viable, novel method for pathogen-specific imaging of Staphylococcus aureus endocarditis. We will employ high affinity PET probes to image murine endocarditis by hybrid PET/MRI. Agent development will focus on clinical feasibility, with the ultimate goal of using PET/MRI detection of staphylocoagulase in valve lesions for the diagnosis of acute endocarditis in patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114477-02
Application #
8672213
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Danthi, Narasimhan
Project Start
2013-06-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$413,582
Indirect Cost
$145,106
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Leuschner, Florian; Courties, Gabriel; Dutta, Partha et al. (2015) Silencing of CCR2 in myocarditis. Eur Heart J 36:1478-88
Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B et al. (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116:407-17
Heidt, Timo; Courties, Gabriel; Dutta, Partha et al. (2014) Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res 115:284-95
Mulder, Willem J M; Jaffer, Farouc A; Fayad, Zahi A et al. (2014) Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med 6:239sr1
Courties, Gabriel; Heidt, Timo; Sebas, Matthew et al. (2014) In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol 63:1556-66
Huang, Jiansheng; Smith, Forrest; Panizzi, Peter (2014) Ordered cleavage of myeloperoxidase ester bonds releases active site heme leading to inactivation of myeloperoxidase by benzoic acid hydrazide analogs. Arch Biochem Biophys 548:74-85
Courties, Gabriel; Moskowitz, Michael A; Nahrendorf, Matthias (2014) The innate immune system after ischemic injury: lessons to be learned from the heart and brain. JAMA Neurol 71:233-6
Nahrendorf, Matthias; Swirski, Filip K (2014) Fluorescent leukocytes enter plaque on the microscope stage. Circ Res 114:740-1
Frantz, Stefan; Nahrendorf, Matthias (2014) Cardiac macrophages and their role in ischaemic heart disease. Cardiovasc Res 102:240-8
Swirski, Filip K; Nahrendorf, Matthias (2014) Do vascular smooth muscle cells differentiate to macrophages in atherosclerotic lesions? Circ Res 115:605-6

Showing the most recent 10 out of 16 publications