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Staphylococcus aureus is a gram-positive bacterium that is causative agent of a variety of human diseases ranging from minor skin infections to more serious and potentially life-threatening diseases like sepsis, endocarditis, septic arthritis, and peritonitis. These infections are of high prevalence in the healthcare setting although S. aureus is being isolated more frequently in the community. S. aureus has evolved many factors that allow the bacterium to engage components of the host coagulation system, including proteins that control fibrin deposition [coagulase (CoA) and von Willebrand Factor binding protein (vWbp)], fibrin degradation (staphylokinase), and binding (clumping factor A). This indicates that coagulation factors, but particularly fibrinogen, is important for host-pathogen interactions during S. aureus infection. However, there is an interesting dichotomy in the effect of host-pathogen interaction in disease that is dependent on the route of infection. In the context of S. aureus peritonitis, fibrin(ogen) is a critical component of host defense. We hypothesized that elimination of S. aureus from the peritoneal cavity is dependent on fibrin matrix engagement of host immune cells and bacteria. To test this hypothesis, we used a model of acute S. aureus peritonitis where we infected mice with genetically imposed deficiencies or mutations in prothrombin and fibrinogen. Collectively, our findings suggest that the host antimicrobial response against S. aureus peritonitis works through a fibrin(ogen)-dependent mechanism where pro-coagulant function by bacterial coagulase vWbp mediates the formation of a fibrin matrix that is engaged by both macrophages (via alpha M Beta 2) and S. aureus (via ClfA). The formation of the complex results in effective elimination of S. aureus from the peritoneal cavity, limiting dissemination and improving host survival. In the context of bacteremia, however, fibrin(ogen)-S. aureus interactions are a key determinant of bacterial virulence. Previous studies showed that elimination of the ClfA-binding motif on fibrinogen (i.e., Fib gamma delta 5), results in reduced bacterial colonization in organs, reduced systemic inflammation and reduced tissue damage, which ultimately leads to improved host survival. We hypothesized that fibrinogen gamma’ could be a potential therapeutic aid for S. aureus bacteremia as it is functionally similar to fibrinogen gamma delta 5. While fibrinogen gamma’ was able to support bacterial adhesion and clumping, treatment with fibrinogen gamma’ improved host survival following S. aureus bacteremia in both prophylactic and therapeutic models. Collectively, these findings suggest fibrinogen plays an important role in S. aureus infection by modulating both host defense and bacterial virulence. |
