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.

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

“…ClfB appears to recognize a glycine and serine rich motif, GSSGXGXXG, that is also present in loricrin, explaining how it is able to bind to several different ligands with similar affinities (Mulcahy et al, 2012; Xiang et al, 2012). Of note, mouse fibrinogen lacks this motif, explaining why ClfB binds to human fibrinogen with higher affinity (Ko and Flick, 2016). Studies in both mice and humans have shown that ClfB is important for nasal colonization (Schaffer et al, 2006; Wertheim et al, 2008), and this appears to be primarily due to its ability to bind loricrin (Mulcahy et al, 2012).…”

“…The sdrE isoform is more common and is found in ~55–65% of clinical isolates (Li et al, 2013; Peacock et al, 2002; Yu et al, 2012). The function of SdrE is less clear, although preliminary results suggest that it also binds fibrinogen, with a higher affinity for non-human fibrinogen (Ko and Flick, 2016). In addition, SdrE has been reported to bind to complement regulator factor H (Sharp et al, 2012), and it can also promote platelet aggregation (O’Brien et al, 2002a).…”

“…Interactions of the immune system with fibrin and fibrinogen are complex, and in some instances the presence of fibrinogen in infected sites clearly promotes containment and clearance of invading staphylococci (Ko and Flick, 2016). However, in most settings S. aureus takes advantage of host fibrinogen and hijacks the human coagulation system for its own survival.…”

“…However, in most settings S. aureus takes advantage of host fibrinogen and hijacks the human coagulation system for its own survival. The anti-phagocytic effect of fibrinogen bound on the surface of S. aureus has been well established (Higgins et al, 2006; Ko and Flick, 2016). There are probably several distinct mechanisms responsible for this outcome, such as shielding opsonins from recognition by immune cells using a fibrinogen layer (Ko and Flick, 2016), or the recruitment of factor H, which binds directly to fibrinogen and inhibits complement activation (Horstmann et al, 1992).…”

“…The anti-phagocytic effect of fibrinogen bound on the surface of S. aureus has been well established (Higgins et al, 2006; Ko and Flick, 2016). There are probably several distinct mechanisms responsible for this outcome, such as shielding opsonins from recognition by immune cells using a fibrinogen layer (Ko and Flick, 2016), or the recruitment of factor H, which binds directly to fibrinogen and inhibits complement activation (Horstmann et al, 1992). While in certain experimental settings the effect of fibrinogen binding and bacterial clumping on phagocytosis seems to be minimal (Palmqvist et al, 2004b), the protective potential of fibrinogen on staphylococcal surfaces has been confirmed in most studies (Ko and Flick, 2016).…”