In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation

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Abstract
Infection by coagulase-positive Staphylococcus aureus (S. aureus) is the most common cause of acute endocarditis, a destructive and progressive condition of heart valves. Here, Peter Panizzi and his colleagues have developed a targeted, noninvasive fluorescence or positron emission technology imaging strategy that uses an engineered analog of prothrombin that can detect S. aureus in vivo in the endocarditic vegetations that form as a result of bacterial colonization. Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.