The human fibrinolytic system is a target for the staphylococcal metalloprotease aureolysin

Abstract

The major opportunistic pathogen Staphylococcus aureus utilizes the human fibrinolytic system for invasion and spread via plasmin(ogen) binding and non-proteolytic activation. Because S. aureus secretes several proteases recently proposed as virulence factors, we explored whether these enzymes could add to the activation of the host's fibrinolytic system. Exposure of human pro-urokinase [pro-uPA (where uPA is urokinase-type plasminogen activator)] to conditioned growth media from staphylococcal reference strains results in an EDTA-sensitive conversion of the single-chain zymogen into its two-chain active form, an activity not observed in an aureolysin-deficient strain. Using purified aureolysin, we verified the capacity of this thermolysin-like metalloprotease to activate pro-uPA, with a 2.6 x 10(3) M(-1) x s(-1) catalytic efficiency. Moreover, activation also occurs in the presence of human plasma, as well as in conditioned growth media from clinical isolates. Finally, we establish that aureolysin (i) converts plasminogen into angiostatin and mini-plasminogen, the latter retaining its capacity to be activated by uPA and to hydrolyse fibrin, (ii) degrades the plasminogen activator inhibitor-1, and (iii) abrogates the inhibitory activity of alpha(2)-antiplasmin. Altogether, we propose that, in parallel with the staphylokinase-dependent activation of plasminogen, aureolysin may contribute significantly to the activation of the fibrinolytic system by S. aureus, and thus may promote bacterial spread and invasion.

The Omptins ofYersinia pestisandSalmonella entericaCleave the Reactive Center Loop of Plasminogen Activator Inhibitor 1

“…Degradation of PAI-1 has earlier been observed with the serine protease subtilisin NAT of Bacillus subtilis and the thermolysin-like metalloproteinases aureolysin of Staphylococcus aureus and LasB of Pseudomonas aeruginosa (2,3,7,65). These are extracellularly secreted enzymes, and their cleavage patterns with PAI-1 and plasminogen are different from those of Pla and PgtE.…”

Complement C3 is a novel plasma clot component with anti-fibrinolytic properties

“…Impaired fibrinolysis would also impair bacterial migration through the fibrin mesh; the importance of this is supported by exploitation of the fibrinolytic system by certain bacteria to facilitate invasion. [40][41][42] Limitations of the study The predominance of highly cross-linked fibrin multimers resulted in difficulty in resolving high molecular weight complexes by both 1-DE and 2-DE approaches. The predominance of fibrin isoforms across the molecular weight and pI range by 2-DE approaches due to the very nature of the plasma clot led to a relatively small number of nonfibrin components being detected with significant MOWSE scores.…”

Haemophilus influenzae Uses the Surface Protein E To Acquire Human Plasminogen and To Evade Innate Immunity

“…In addition to H. influenzae, the Gram-negative pathogenic bacteria B. burgdorferi (31,45), P. aeruginosa (33), and H. pylori (35), the Gram-positive bacteria S. pneumoniae (30) and S. aureus (46), and also human pathogenic fungi, including C. albicans (36,47) and A. fumigatus (48), bind plasminogen. H. influenzae, similar to many microbial pathogens, expresses at least two plasminogen binding proteins, PE and aspartase.…”