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) it initiates the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin detected S. aureus in endocarditic vegetations via noninvasive fluorescence or PET imaging. These prothrombin derivatives bound to 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.

Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense

“…[51][52][53][54][55] Interestingly, in the setting of intravenous S aureus infection (bacteremia), fibrinogen supports pathogen virulence and investigator-imposed fibrinogen deficiency improves host survival, 14 whereas in the setting of S aureus peritonitis, fibrinogen diminishes pathogen virulence and investigator-imposed fibrinogen deficiency impedes bacterial clearance and reduces host survival. 15 An impediment in the clearance of S aureus in the peritoneal cavity was also documented for mice carrying a mutant form of fibrinogen lacking the a M b 2 binding motif but maintaining full clotting function.…”

N-Acetylglucosaminylation of Serine-Aspartate Repeat Proteins Promotes Staphylococcus aureus Bloodstream Infection

“…Agglutination with fibrin fibrils protects staphylococci from phagocytes and promotes the formation of infectious thrombi that contribute to the lethal outcome of staphylococcal sepsis in mice (4,10). Staphylococcal agglutination is also essential for the pathogenesis of infectious endocarditis and the formation of purulent abscess lesions, which promote bacterial persistence and dissemination in host tissues (11)(12)(13).…”

Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection

“…These models include but are not limited to intravenous challenge with staphylococci to induce sepsis (12,29) or endocarditis (44), subcutaneous injection of staphylococci to generate skin and soft tissue infections (10,52), and intranasal instillation of staphylococci to induce pneumonia (5). The identification of discrete, diseasespecific virulence factors of S. aureus in each of these models underscores the versatility of the pathogen (8,9,11).…”