Fibrinogen Is at the Interface of Host Defense and Pathogen Virulence in Staphylococcus aureus Infection

Abstract

Fibrinogen not only plays a pivotal role in hemostasis but also serves key roles in antimicrobial host defense. As a rapidly assembled provisional matrix protein, fibrin(ogen) can function as an early line of host protection by limiting bacterial growth, suppressing dissemination of microbes to distant sites, and mediating host bacterial killing. Fibrinogen-mediated host antimicrobial activity occurs predominantly through two general mechanisms, namely, fibrin matrices functioning as a protective barrier and fibrin(ogen) directly or indirectly driving host protective immune function. The potential of fibrin to limit bacterial infection and disease has been countered by numerous bacterial species evolving and maintaining virulence factors that engage hemostatic system components within vertebrate hosts. Bacterial factors have been isolated that simply bind fibrinogen or fibrin, promote fibrin polymer formation, or promote fibrin dissolution. Staphylococcus aureus is an opportunistic gram-positive bacterium, the causative agent of a wide range of human infectious diseases, and a prime example of a pathogen exquisitely sensitive to host fibrinogen. Indeed, current data suggest fibrinogen serves as a context-dependent determinant of host defense or pathogen virulence in Staphylococcus infection whose ultimate contribution is dictated by the expression of S. aureus virulence factors, the path of infection, and the tissue microenvironment.

Fig. 1

Fibrinogen-binding S. aureus microbial surface components recognizing adhesive matrix molecules (MSCRAMMs). Schematic presentation of the domain organization of the fibrinogen-binding S. aureus MSCRAMMs. The A region contains three separately folded domains, which are known as N1, N2, and N3 subdomains. N2 and N3 subdomains structurally form immunoglobulin G–like folds that bind fibrinogen by the “dock, lock and latch” mechanism. The S. aureus surface protein SdrE and bone sialoprotein–binding protein (Bbp) contain additional three B repeats that are located between the A region and the serine–aspartate repeat region. Fibronectin-binding protein A (FnBPA) and FnBPB have A regions that are structurally and functionally similar to the A region of the Clf or Sdr group and that is followed by tandemly repeated fibronectin-binding domains (11 in FnBPA, 10 in FnBPB).

Fig. 2

Fibrinogen-binding S. aureus secretable expanded repertoire adhesive molecules (SERAMs). Schematic presentation of the domain organization of the fibrinogen-binding S. aureus SERAMs. The N-terminal intrinsically disordered region of extracellular fibrinogen-binding protein (Efb) harbors two fibrinogen-binding sites, whereas the C-terminal ordered region binds complement component C3. Extracellular matrix–binding protein (Emp) overall does not adopt a defined structure. Extracellular adherence protein (Eap) harbors six repeated domains (1–6) of approximately ~97 amino acids. Coagulase (Coa) and von Willebrand factor–binding protein (vWbp) are homologs that both contain D1D2 domains that activate prothrombin without proteolytic cleavage. The C-terminal part of Coa contains tandem repeats (R) of 27 amino acids and harbors predominant fibrinogen-binding sites. The numbers of repeats vary from five to eight among different strains of S. aureus. The C-terminal of vWbp contains von Willebrand factor–binding site of 26 amino acids.

Fig. 3

Identification of the binding sites for S. aureus fibrinogen directed MSCRAMMs. Clumping factor A (ClfA), Fibronectin-binding protein A, and B (FnBPA and FnBPB) recognize the C-terminal of the fibrinogen γ chain, whereas clumping factor (ClfB) binds to C-terminal of the α chain. Bbp binds to C-terminus of the α chain. MSCRAMMs, microbial surface components recognizing adhesive matrix molecules.