Host Fibrinogen and the S. Aureus-Encoded Procoagulant Vwbp Are Context-Dependent Determinants of Bacterial Virulence.

Abstract 1152

Microbial pathogens frequently express bacterial products that are specifically designed to engage hemostatic system components in their vertebrate hosts. Staphylococcus aureus has evolved a particularly impressive repertoire of factors to control fibrin deposition, dissolution, and binding, including two bacterial products that form proteolytically active procoagulant complexes with prothrombin, staphylocoagulase (Coa) and von Willebrand factor binding protein (vWbp). These findings support the working hypothesis that hemostatic factors, in general, and fibrinogen, in particular, are likely to be important determinants of S. aureus virulence/host defense. To directly explore the role of fibrin(ogen) in host inflammatory/antimicrobial processes, a comparative analysis of bacterial clearance was done in control and fibrinogen-deficient mice in the context of S. aureus peritonitis. Control mice challenged with 10⁹ CFU of S. aureus were found to efficiently clear S. aureus within the peritoneal cavity and eliminated ∼99.5% of bacterial CFUs within 20 minutes, whereas fibrin(ogen)-deficient mice exhibited little capacity to clear the microbe, even after several hours. Consistent with these findings, fibrinogen-deficient mice challenged with S. aureus peritonitis also exhibited a poor survival profile relative to control animals. More detailed studies to define the mechanism(s) underlying the rapid, fibrin(ogen)-dependent clearance of S. aureus have thus far excluded a critical contribution of host T cells, B cells, neutrophils, immunglobulins, complement, toll-like receptor signaling pathways, and the bacterial fibrinogen receptor clumping factor A (ClfA). However, mice carrying low levels of circulating prothrombin or expressing a mutant form of fibrinogen that cannot be converted to fibrin, exhibited a profound defect in S. aureus clearance following i.p. infection, suggesting a central role for fibrin polymer in the implementation of an effective antimicrobial program. Although fibrin formation is necessary, it is not sufficient for efficient bacterial clearance; Fibγ^390-396A mice retaining full clotting function, but lacking the leukocyte integrin Mac-1 binding motif, also exhibit an impediment in bacterial clearance relative to wild-type mice. Complementary studies of S. aureus mutants deficient in bacterial procoagulants indicate that vWbp, but not Coa, is a fundamental determinant of bacterial clearance in this peritonitis model. Remarkably, bacterial procoagulant vWbp is distinctly counter-productive to the microbe in the context of peritonitis and supports the rapid, fibrin(ogen)-dependent clearance of intraperitoneal S. aureus. Based on findings indicating that host fibrinogen and bacterial factors that engage fibrin(ogen) support S. aureus virulence in other infection settings, the present findings suggest that host hemostatic factors and the bacterial procoagulant vWbp are likely to be context-dependent determinants of bacterial virulence. A better understanding of the interactions between bacterial proteins and host hemostatic factors, as well as interactions between the host hemostatic and inflammatory/immune systems, may well reveal novel therapeutic approaches for limiting microbial infections and sepsis.