PMID:22028651

Citation	McAdow, M, Kim, HK, Dedent, AC, Hendrickx, AP, Schneewind, O and Missiakas, DM (2011) Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog. 7:e1002307
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.
Links	PubMed PMC3197598 Online version:10.1371/journal.ppat.1002307
Keywords	Agglutination/physiology; Animals; Antibodies, Neutralizing/blood; Antibodies, Neutralizing/immunology; Antithrombins/pharmacology; Bacterial Proteins/metabolism; Carrier Proteins/metabolism; Coagulants/metabolism; Coagulase/immunology; Coagulase/metabolism; Disease Models, Animal; Heart/microbiology; Host-Pathogen Interactions; Humans; Immunization, Passive; Longevity/drug effects; Mice; Mice, Inbred BALB C; Myocardium/pathology; Protein Binding; Sepsis/immunology; Sepsis/microbiology; Sepsis/prevention & control; Staphylococcal Infections/immunology; Staphylococcal Infections/microbiology; Staphylococcus aureus/metabolism; Staphylococcus aureus/pathogenicity; Staphylococcus aureus/ultrastructure; von Willebrand Factor/immunology; von Willebrand Factor/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
STAAE:CLFA	involved_in	GO:0009405: pathogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
STAAE:CLFA		GO:0009405: pathogenesis	ECO:0000315:		P		Fig. 1 Clumping Factor A has shown to be the most important of a three gene system: clfA, vwb, and coa. Mutations to clfA severely impaired agglutination.	complete CACAO 9596

References

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