The Complex Fibrinogen Interactions of the Staphylococcus aureus Coagulases

Abstract

The two coagulases, von Willebrand factor binding protein (vWbp) and Coagulase (Coa), are critical virulence factors in several animal models of invasive Staphylococcus aureus ( S. aureus ) infections. These proteins are part of an intricate system of proteins that S. aureus uses to assemble a fibrinogen (Fg)/fibrin protective shield surrounding itself. This shield allows the microorganism to evade clearance by the host phagocytic cells. The coagulases can non-proteolytically activate the zymogen prothrombin to convert Fg to fibrin and promote the Fg/fibrin shield formation. The coagulases also bind directly to Fg and the interaction between Coa and Fg has been previously characterized in some detail. However, the mechanism(s) by which vWbp interacts with Fg remains unclear. Here, we show that vWbp and Coa have distinct interactions with Fg, despite being structurally similar. Coa binds with a significantly higher affinity to soluble Fg than to Fg coated on a plastic surface, whereas vWbp demonstrates no preference between the two forms of Fg. The two coagulases appear to target different sites on Fg, as they do not compete with each other in binding to Fg. Similar to Coa, both the N- and C-terminal halves of vWbp (vWbp-N, vWbp-C, respectively) harbor Fg-binding activities. The higher affinity Fg-binding activity resides in vWbp-N; whereas, the C-terminal region of Coa encompasses the major Fg-binding activity. Peptides constituting the previously identified Coa/Efb 1 Fg-binding motif fail to inhibit vWbp-C from binding to Fg, indicating that vWbp-C lacks a functional homolog to this motif. Interestingly, the N-terminal prothrombin-binding domains of both coagulases recognize the Fg β-chain, but they appear to interact with different sequence motifs in the host protein. Collectively, our data provide insight into the complex interactions between Fg and the S. aureus coagulases.

Quorum Sensing and Toxin Production in Staphylococcus aureus Osteomyelitis: Pathogenesis and Paradox

“…Despite their structural similarities, vWbp functions through a mechanism that differs from Coa. Coa binds primarily to soluble fibrinogen, while vWbp does not demonstrate binding preference between soluble and surface-bound fibrinogen, resulting in a lack of competition for binding [98]. While Agr quorum sensing is necessary for late-stage microcolony dispersal, vWbp facilitates formation of a microcolony-associated meshwork for bacterial persistence [97].…”

Antibiotic resistance profiles and population structure of disease-associatedStaphylococcus aureusinfecting patients in Fort Portal Regional Referral Hospital, Western Uganda

“…An association between CC152 and PVL has been noted previously [56]. Coa is a long-established virulence factor of S. aureus that is able to induce blood coagulation by interacting with fibrinogen and prothrombin [60]. Interestingly, von Willebrand factor binding protein, encoded by vWbp , exhibits multiple similarities in terms of coagulation induction function to Coa [60].…”

Fibrin Matrices as (Injectable) Biomaterials: Formation, Clinical Use, and Molecular Engineering

“…Fibrin hydrogels have been applied in wound dressings to release antimicrobial agents, that can range from established antimicrobial drugs, to bacteriophages, and even the very cells still present in leucocyte‐ and platelet‐rich fibrin . The interactions of fibrin(ogen) itself with bacteria, however, have not been completely clarified, and there are evidences pointing to opposite directions:for example, on one hand Staphylococcus aureus can activate prothrombin via coagulases to form fibrin “shields” that help its evasion from phagocytic cells; on the other hand the adhesion and subsequent clumping of S. aureus to fibrin(ogen), mediated by clumping factor A, has been shown to facilitate the clearance of infection after peritonitis…”