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4D Multimodality Imaging of Citrobacter rodentium Infections in Mice
Published on: August 13, 2013
Multimodal imaging of bacterial-host interface in mice and piglets with Staphylococcus aureus endocarditis
Peter Panizzi1, Marvin Krohn-Grimberghe2,3, Edmund Keliher2
1Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
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.
Insights
New imaging tools and therapies target Staphylococcus aureus virulence factors in bacterial endocarditis. This approach disrupts protective fibrin barriers, enhances immune response, and improves survival in preclinical models.
Area of Science:
- Infectious Diseases
- Molecular Imaging
- Immunotherapy
Background:
- Acute bacterial endocarditis, often caused by Staphylococcus aureus, is a life-threatening condition.
- S. aureus forms a protective fibrin barrier using virulence factors like staphylocoagulase, evading antibiotics and host immunity.
- Targeting these virulence factors offers a novel therapeutic strategy for endocarditis.
Purpose of the Study:
- To develop and validate multimodal molecular imaging agents and therapeutics targeting the host-pathogen interface in S. aureus endocarditis.
- To probe the efficacy of neutralizing key S. aureus virulence factors using advanced imaging techniques.
- To establish a preclinical framework for evaluating novel endocarditis therapies.
Main Methods:
- Development of small-molecule optical and positron emission tomography (PET) imaging agents targeting active thrombin within fibrin-rich bacterial vegetations.
- Preclinical studies in mouse models of S. aureus endocarditis using antibody-based therapies against staphylocoagulase and von Willebrand factor-binding protein.
- In vivo monitoring of therapeutic response using optical imaging and assessment of survival rates.
- Translation of imaging techniques to a piglet model of S. aureus endocarditis using clinical PET/magnetic resonance imaging.
Main Results:
- Novel imaging agents successfully bound to heart valve vegetations in mice, visualizing the fibrin-rich environment.
- Therapy neutralizing staphylocoagulase and von Willebrand factor-binding protein deactivated bacterial defenses, reduced in vivo imaging signals, and improved survival in mice.
- Successful imaging of S. aureus endocarditis in piglets using clinical PET/magnetic resonance imaging.
Conclusions:
- Targeting S. aureus virulence factors represents a promising avenue for adjuvant immunotherapy in bacterial endocarditis.
- Developed molecular imaging tools provide efficient methods for monitoring therapeutic responses to novel drug classes in infectious diseases.
- This study establishes a foundation for improved diagnosis and treatment strategies for acute bacterial endocarditis.
