Research ArticleImaging

Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis

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Science Translational Medicine  04 Nov 2020:
Vol. 12, Issue 568, eaay2104
DOI: 10.1126/scitranslmed.aay2104

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Imaging infection

Infection of the lining of the heart and valves (endocarditis) can be difficult to treat, and proper identification of the causal pathogen is very important. Panizzi et al. developed small-molecule imaging agents based on dabigatran, a thrombin inhibitor, to visualize Staphylococcus aureus endocarditis. Positron emission tomography and intravital microscopy using the imaging agents revealed that treatment with neutralizing antibodies reduced thrombin deposition and impeded S. aureus endocarditis growth in mice. The imaging agents could also be used to visualize infections in piglets. These imaging tools could help monitor disease progression and response to treatment.

Abstract

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

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