Fibrin(ogen)-Pathogen Interactions Support Antimicrobial Host Defense Following Staphylococcus Aureus Peritonitis Infection

Staphylococcus aureus is a common gram-positive bacterium that is a frequent cause of community and hospital-acquired infections. The emergence of antibiotic resistant S. aureus hashighlighted a renewed need to better understand host-pathogen interactions for defining novel treatment strategies. The clotting factor fibrinogen is a target of several S. aureus virulence factors. Clumping factor A (ClfA) is a well characterized fibrin(ogen) binding protein known to mediate bacterial adhesion and clumping in blood plasma and has been shown to play an important role in several types of S aureus infections. Studies using Fib^-/- (fibrinogen deficient) and Fib^AEK (mice expressing fibrinogen unable to form a fibrin polymer) indicated that fibrinogen and subsequent fibrin polymer formation are critical for clearance of USA300 S. aureus following peritonitis. Here, we tested the hypothesis that ClfA-fibrin(ogen)interactions are a key mechanistic feature of host antimicrobial function following S. aureus peritonitis. Analyses were performed with Fibγ^Δ5 mutant mice, which express a mutant form of fibrinogen lacking the final 5 amino acids of the g chain encoding the bacterial ClfA binding motif. In vitro studies confirmed that fibrinogen^WT supported robust bacterial adhesion and clumping whereas a complete absence of adhesion and clumping was observed using fibrinogenγ^Δ5. Infection studies of WT and Fibγ^Δ5 mice revealed that ClfA-mediated, fibrin(ogen)- S. aureus interactions are an important determinant of host antimicrobial function in the context of peritonitis. Taken together, these data indicate that direct, ClfA-mediated binding of bacteria to fibrin(ogen) is a critical mechanistic component of host antimicrobial function following S. aureus peritonitis.