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

PLoS Pathogens

Hwan Keun Kim¹  Molly McAdow¹  Olaf Schneewind¹  Dominique M. Missiakas¹  Andrea C. DeDent¹  Antoni P. A. Hendrickx¹ 

[1] Department of Microbiology, University of Chicago, Chicago, Illinois, United States of America

关键词: Staphylococcus aureus;    Sepsis;    Staphylococcus;    Fibrinogen;    Fibrin;    Antibodies;    Heart;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1002307

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY