SAK

Related Reading

Introduction

Staphylokinase (SAK) is expressed by lysogenic strains of Staphylococcus aureus and is a 136 amino acid long bacteriophage-encoded protein. Current research on the mechanism of action of this enzyme during bacterial infection is based on its interaction with host proteins, α-defensins and plasminogen. α-defensins are bactericidal peptides derived from human neutrophils, and the binding of staphylokinase to them eliminates the bactericidal properties, thus making staphylokinase an important tool for staphylococcus resistance to host innate immunity. The complex binding between staphylokinase and plasminogen forms active plasmin, a broad-spectrum proteolytic enzyme that facilitates bacterial penetration into the surrounding tissues. Studies have shown high levels of staphylokinase expression in clinical isolates of skin and mucosal origin and lower levels in isolates invading internal organs. Subsequent sepsis studies using isogenic S. aureus strains also supported this notion of increased bacterial load in the absence of staphylokinase production. Staphylokinase facilitates the symbiosis of staphylococci with the host, making it an important colonization factor.

Biological function of staphylokinase

Staphylokinase is a virulence factor of Staphylococci, and its mechanism of action is thought to be due to its interaction with plasminogen and α-defensins. Staphylokinase binding to plasminogen affects bacterial invasion of host tissues. There are currently several different models of staphylokinase-mediated bacterial invasion. The staphylokinase-plasmin(ogen) complex may first bind to the fibrin net around the infection focus or abscess and cleave, helping staphylococci to enter deeper host tissues. Plasmin is a serine protease whose substrates include matrix proteins such as fibrin, elastin, and collagen. Plasmin is also thought to be a matrix metalloproteinase activator that promotes the lysis of surrounding tissue by plasmin. Staphylokinase enhances bacterial resistance to phagocytosis by interacting with short cationic peptides produced by human neutrophils (HNPs). HNPs are an important component of the innate immune response and possess excellent bactericidal and antiviral properties (Figure 1). Staphylokinase is an efficient absorber of HNPs, which has several binding sites for HNPs, even in the presence of excess HNPs.

Figure 1. The bactericidal effect of α-defensins on Staphylococcus aureus strains depending on their production of staphylokinase (Bokarewa, M.; et al. 2006)

Impact of staphylokinase expression during staphylococcal infection

The frequency of staphylokinase expression varied between 4% and 100% among different S. aureus isolates. The production of staphylokinase is detected in the laboratory by analyzing its ability to activate plasminogen and induce fibrinolysis. The sensitivity of plasminogen to staphylokinase activation differs significantly among different mammalian species, which may partly explain the variability in the frequency of staphylokinase expression. Staphylokinase may attach to bacterial cell wall through its binding to plasminogen. However, the possibility of staphylokinase directly adhering to the bacterial surface cannot be completely ruled out. Staphylokinase production was shown in nearly all staphylococcal isolates obtained from skin and mucosa (Figure 2). Notably, the presence of coagulase was also detected in all staphylokinase-producing isolates, indicating that the production of these proteins is not mutually exclusive.

Figure 2. Production of staphylokinase by S. aureus isolated from nasal secrete of healthy individuals (n = 98 inhabitants of Goteborg, Sweden, and n = 48 inhabitants of Durham, USA) and from blood cultures of patients with sepsis (Bokarewa, M.; et al. 2006)

Conclusions

These results suggest that the production of staphylokinase may be necessary for the persistence of staphylococcal on the host skin and mucosa. Although staphylokinase promotes bacterial spread to surrounding tissues, staphylokinase may prevent distant migration to internal organs through circulating blood. Therefore, staphylokinase secretion can act as a signal for bacteria to move from the blood to the tissues. Since most patients with staphylococcal bacteremia and sepsis infected the strains identical to their nasal isolates, staphylokinase expression may be an important factor in bacterial persistence in susceptible groups of immunocompromised and elderly patients.