Bacterial Plasminogen Receptors Utilize Host Plasminogen System for Effective Invasion and Dissemination

Abstract

In order for invasive pathogens to migrate beyond the site of infection, host physiological barriers such as the extracellular matrix, the basement membrane, and encapsulating fibrin network must be degraded. To circumvent these impediments, proteolytic enzymes facilitate the dissemination of the microorganism. Recruitment of host proteases to the bacterial surface represents a particularly effective mechanism for enhancing invasiveness. Plasmin is a broad spectrum serine protease that degrades fibrin, extracellular matrices, and connective tissue. A large number of pathogens express plasminogen receptors which immobilize plasmin(ogen) on the bacterial surface. Surface-bound plasminogen is then activated by plasminogen activators to plasmin through limited proteolysis thus triggering the development of a proteolytic surface on the bacteria and eventually assisting the spread of bacteria. The host hemostatic system plays an important role in systemic infection. The interplay between hemostatic processes such as coagulation and fibrinolysis and the inflammatory response constitutes essential components of host defense and bacterial invasion. The goal of this paper is to highlight mechanisms whereby pathogenic bacteria, by engaging surface receptors, utilize and exploit the host plasminogen and fibrinolytic system for the successful dissemination within the host.

Dimerization Is Not a Determining Factor for Functional High Affinity Human Plasminogen Binding by the Group A Streptococcal Virulence Factor PAM and Is Mediated by Specific Residues within the PAM a1a2 Domain

“…Of four well studied hPg-binding proteins that have been described (39), hPg binding M and M-like protein (PAM) is the best characterized (40). PAM has long been recognized as a major virulence factor of skin-tropic GAS strains.…”

Molecular Interactions of Human Plasminogen with Fibronectin-binding Protein B (FnBPB), a Fibrinogen/Fibronectin-binding Protein from Staphylococcus aureus

“…Proteolytic activation of PLG to plasmin occurs through cleavage of the Arg 561 -Val 562 peptide bond in the catalytic domain by the tissue plasminogen activator (t-PA) and urokinase plasminogen activator. The cleavage results in the formation of active plasmin enzyme that contains a serine protease active site in the C-terminal region (23,26,27).…”

Lipoprotein(a) Binds to C-terminal Lysine Residues of Recombinant Enolase Derived from Group A <i>Streptococcus</i>

“…GAS uses these receptors to secure human Plg on its surface subsequently activates bacterium-associated Plg to plasmin by its Plg activator (streptokinase) and/or host activators (uPA and tPA) [5]. This bacterial cell-associated plasmin may facilitate the dissemination of GAS [4,6]. In addition, SEN has been demonstrated to contain several lysine residues including two C-terminal and two internal lysine residues [7], which are responsible for the binding to Plg.…”

“…However, the biological function of Lp(a) is still unknown although Lp(a) has been studied extensively since it was identified in 1963 [9][10][11]. Besides other domains Apo(a) contains ten classes of Plg kringle IV-like domains designated KIV [1][2][3][4][5][6][7][8][9][10] [12], of which KIV 10 contains a relatively strong LBS. KIV 10 may competitively inhibit the binding between Plg and plasmin-modified fibrinogen [13].…”