The Virulence of S. Aureus Is Supported by Host Fibrinogen and Its Bacterial Receptor ClfA in the Context of Bacteremia.

Abstract 3188

Poster Board III-125

The pervasive gram-positive bacterial pathogen Staphylococcus aureus has evolved and maintained a number of proteins that directly engage the host hemostatic system, including factors that directly interact with the host coagulation factor fibrinogen. Here, we investigate the hypothesis that binding of host fibrin(ogen) through the bacterial fibrinogen receptor, clumping factor A (ClfA), significantly contributes to virulence in the context of acute bacteremia. To directly test this view, we compared survival following intravenous injection of ClfA-postive S. aureus into fibrinogen-deficient and control mice. The genetic elimination of fibrinogen resulted in a dramatic prolongation in survival relative to fibrinogen sufficient control animals. To determine if this prolongation in survival was related to the ability of the pathogen to directly bind fibrinogen, we performed identical survival studies in mice expressing a mutant form of fibrinogen that retains normal clotting function but lacks the binding motif for ClfA located on the fibrinogen γ chain (termed Fib γ^Δ5). A profound survival advantage was observed for Fib γ^Δ5 mice relative to wild-type animals over a wide bacterial dose range corresponding to an LD₅₀ to an LD₁₀₀ for control animals. This difference in survival appeared to be linked to ClfA, as control and Fib γ^Δ5 mice revealed an identical survival profile when infected with ClfA-deficient S. aureus. Analysis of bacterial burden after infection in various organ systems revealed that ClfA-positive S. aureus rapidly marginalized from the circulation and colonized target organs in mice of both genotypes. The highest numbers of colony forming units (cfu) were found in the heart and kidney of challenged mice, but the cfu values observed in both of these tissues were significantly reduced in Fib γ^Δ5 mice, relative to control animals at 24 and 48 hours after initial infection. The cfu values also tended to be reduced in Fib γ^Δ5 mice over wild-type controls in the liver, lung, spleen and blood, but this difference did not achieve statistical significance. Complementary studies revealed a comparable systemic inflammatory response in control and Fib γ^Δ5 animals following initial infection; plasma levels of Il-6 and fibrinogen (an established acute phase reactant) were similarly elevated in both genotypes following infection. Notably, increased histological evidence of cardiac damage secondary to S. aureus bacteremia in wild-type mice relative to Fib γ^Δ5 animals correlated with significantly higher plasma levels of markers of cardiac damage (i.e., lactose dehydrogenase and muscle creatine kinase enzyme activity) 48 hours after infection. These data suggest that bacterial engagement of host fibrinogen via the bacterial fibrinogen receptor ClfA significantly contributes to S. aureus virulence following intravenous infection. Strategies designed to disrupt this interaction may be of significant clinical benefit to limit disease progression in S. aureus sepsis and could be achieved without necessarily compromising host hemostatic function.