title: In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation.
abstract: 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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Panizzi
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Panizzi
authors.forename: Brett
authors.initials: B
authors.lastname: Marinelli
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Edmund
authors.initials: E
authors.lastname: Keliher
authors.forename: Ashoka A
authors.initials: AA
authors.lastname: Maddur
authors.forename: Peter
authors.initials: P
authors.lastname: Waterman
authors.forename: Heather K
authors.initials: HK
authors.lastname: Kroh
authors.forename: Florian
authors.initials: F
authors.lastname: Leuschner
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: Olaf
authors.initials: O
authors.lastname: Schneewind
authors.forename: Paul E
authors.initials: PE
authors.lastname: Bock
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D003030:Coagulase / Q000378:metabolism; D004697:Endocarditis, Bacterial / Q000175:diagnosis*; D051379:Mice; D008856:Microscopy, Fluorescence; D049268:Positron-Emission Tomography; D015202:Protein Engineering; D011516:Prothrombin / Q000378:metabolism*; D053038:Quorum Sensing / Q000502:physiology; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D003030:Coagulase; D011516:Prothrombin