Figure 1.

Host fibrinogen is a determinant of virulence in S. aureus septicemia through a mechanism dependent on the 5 carboxy-terminal residues of the fibrinogen γ chain, a motif critical for ClfA binding. (A) Survival profile of fibrinogen-deficient (N = 8) and wild-type (N = 10) mice challenged with an intravenous injection of 3 × 10⁸ CFUs of S. aureus. Although mice of both genotypes ultimately succumb to infection at these high bacterial doses, note that mice lacking fibrinogen exhibit a significant survival advantage. (B) Comparative survival analysis of cohorts of wild-type and Fibγ^Δ5 mice (N = 10 pairs) challenged with intravenous injection of 3 × 10⁸ CFUs of S. aureus. Note that despite full retention of clotting function, Fibγ^Δ5 mice exhibit a distinct survival advantage over control mice. (C) Comparative survival analysis of wild-type and Fibγ^390-396A mice challenged with intravenous injection of 3 × 10⁸ CFUs of S. aureus. Survival statistics were calculated by Kaplan-Meier log rank analysis. (D) Coomassie blue-stained sodium dodecyl sulfate–polyacrylamide gel electrophoresis gel (reducing conditions) of affinity-purified fibrinogen preparations from wild-type and Fibγ^Δ5 mice. (E) Fibrinogen-dependent clumping of ClfA⁺ S. aureus as a function fibrinogen concentration with wild-type (WT) fibrinogen and fibrinogen-γ^Δ5. Note that bacterial clumping was readily observed by simple inspection when bacterial suspensions were combined with wild-type fibrinogen at concentrations as low as 1 to 2 μg/mL. In contrast, S. aureus suspensions combined with fibrinogen-γ^Δ5 failed to support bacterial clumping at any fibrinogen concentration, including concentrations as high as 500 μg/mL. (F, G) Adhesion of wild-type, ClfA⁻, ClfB⁻, and ClfA⁻ClfB⁻ S. aureus to immobilized wild-type fibrinogen (F) and fibrinogen-γ^Δ5 (G). Data are expressed as the mean ± standard deviation at each fibrinogen concentration.