Preventing Staphylococcus aureus Sepsis through the Inhibition of Its Agglutination in Blood

Abstract

Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. When suspended in human or animal plasma, staphylococci are known to agglutinate, however the bacterial factors responsible for agglutination and their possible contribution to disease pathogenesis have not yet been revealed. Using a mouse model for S. aureus sepsis, we report here that staphylococcal agglutination in blood was associated with a lethal outcome of this disease. Three secreted products of staphylococci - coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) – were required for agglutination. Coa and vWbp activate prothrombin to cleave fibrinogen, whereas ClfA allowed staphylococci to associate with the resulting fibrin cables. All three virulence genes promoted the formation of thromboembolic lesions in heart tissues. S. aureus agglutination could be disrupted and the lethal outcome of sepsis could be prevented by combining dabigatran-etexilate treatment, which blocked Coa and vWbp activity, with antibodies specific for ClfA. Together these results suggest that the combined administration of direct thrombin inhibitors and ClfA-antibodies that block S. aureus agglutination with fibrin may be useful for the prevention of staphylococcal sepsis in humans.

Author Summary

Staphylococcus aureus secretes factors that perturb blood coagulation in infected hosts. We report here that three bacterial products – coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) - act together and promote agglutination, the association of staphylococci with polymerized fibrin cables. Staphylococcal agglutination was associated with thromboembolic lesions in heart tissues and a lethal outcome of S. aureus sepsis in mice. Inhibition of Coa and vWbp with direct thrombin inhibitors, drugs already approved for the prevention of stroke, as well as passive transfer of antibodies specific for Coa, vWbp and ClfA could prevent the pathogenesis of S. aureus sepsis. These results suggest new preventive and/or therapeutic strategies that may improve the outcome of S. aureus sepsis in humans, a disease that is otherwise associated with high mortality.