Interaction with human plasminogen system turns on proteolytic activity in Streptococcus agalactiae and enhances its virulence in a mouse model

Abstract

Interactions of several microbial pathogens with the plasminogen system increase their invasive potential. In this study, we show that Streptococcus agalactiae binds human plasminogen which can be subsequently activated to plasmin, thus generating a proteolytic bacterium. S. agalactiae binds plasminogen via the direct pathway, using plasminogen receptors, and via the indirect pathway through fibrinogen receptors. The glyceraldehyde-3-phosphate dehydrogenase is one of the S. agalactiae proteins that bind plasminogen. Presence of exogenous activators such as uPA and tPA are required to activate bound plasminogen. Results from competitive inhibition assays indicate that binding is partially mediated through the lysine binding sites of plasminogen. Following plasminogen binding and activation, S. agalactiae is able to degrade in vitro fibronectin, one of the host extracellular matrix proteins. Moreover, incubation of S. agalactiae with either plasminogen alone, or plasminogen plus fibrinogen, in the presence of tPA enhanced its virulence in C57BL/6 mice, suggesting that acquisition of plasmin-like activity by the bacteria increase their invasiveness.

Plasminogen Acquisition and Activation at the Surface of Leptospira Species Lead to Fibronectin Degradation

“…Several invasive gram-positive and gram-negative bacteria have shown the ability to interact with the host PLG system (6,13,19,37,73), a phenomenon that has been extended to viruses (22,38,60) and parasites (68) (23,41,46,47,69,74). In the case of spirochetes, the PAS was studied with several species of Borrelia and with Treponema denticola and was suggested to have an important role during infectiveness (14,16,21,35,58).…”

“…The process for binding to bacterial receptors on the cell surface has been shown for several pathogens to be mediated by the PLG kringle domains through the contained lysinebinding sites (2,10,16,32,33,46,63,68,77,78). Likewise, Leptospira probably interacts with PLG through the lysine residues because the binding and generation of active plasmin on the bacterial surface were inhibited by the presence of the lysine analogue ACA in the reaction.…”

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…Plasminogen is found in plasma and extracellular fluids, and upon activation is converted to plasmin, which degrades the extracellular matrix and may upregulate matrix metalloproteinases that degrade tight junctions (268). In vitro, plasminogen binds to streptococcal glyceraldehyde-3-phosphate dehydrogenase (269)(270)(271). Enolase and choline-binding protein E have also been identified as additional pneumococcal plasminogen-binding proteins (272,273).…”

“…Enolase and choline-binding protein E have also been identified as additional pneumococcal plasminogen-binding proteins (272,273). Once plasminogen is bound to its binding protein, it becomes activated and is subsequently converted to plasmin by exogenous tissue plasminogen activator and urokinase (269,270,274). Plasmin bound to the surfaces of group B streptococci enhanced the ability of bacteria to adhere to and invade HBMECs and induced a significant decrease in transendothelial electrical resistance (275).…”

Skizzle Is a Novel Plasminogen- and Plasmin-binding Protein from Streptococcus agalactiae That Targets Proteins of Human Fibrinolysis to Promote Plasmin Generation

“…Activation of Pg on the cell surface through Pg-binding proteins, such as Pg-binding group A streptococcal M-like protein (group A, C, and G streptococci), glyceraldehyde-3-phosphate dehydrogenase (GAPDH; group A-C streptococci), and ␣-enolase (group A and B streptococci), results in coating of the cell surface with Pg or active Pm (8 -12). A recent study indicated that Pg activation on the surface of S. agalactiae occurs through the GAPDH-bound Pg complex, facilitating GBS virulence and promoting bacterial dissemination in a murine model (10). Secreted Pg-activating proteins, such as SK and staphylokinase (SAK), are not enzymes themselves but form complexes with Pg or Pm to enable proteolytic Pm generation.…”