Streptococcus pneumoniaeCholine-Binding Protein E Interaction with Plasminogen/Plasmin Stimulates Migration across the Extracellular Matrix

Abstract

The virulence mechanisms leading Streptococcus pneumoniae to convert from nasopharyngeal colonization to a tissue-invasive phenotype are still largely unknown. Proliferation of infection requires penetration of the extracellular matrix, which occurs by recruitment of host proteases to the bacterial cell surface. We present evidence supporting the role of choline-binding protein E (CBPE) (a member of the surface-exposed cholinebinding protein family) as an important receptor for human plasminogen, the precursor of plasmin. The results of ligand overlay blot analyses, solid-phase binding assays, and surface plasmon resonance experiments support the idea of an interaction between CBPE and plasminogen. We have shown that the phosphorylcholine esterase (Pce) domain of CBPE interacts with the plasminogen kringle domains. Analysis of the crystal structure of the Pce domain, followed by site-directed mutagenesis, allowed the identification of the plasminogen-binding region composed in part by lysine residues, some of which map in a linear fashion on the surface of the Pce domain. The biological relevance of the CBPE-plasminogen interaction is supported by the fact that, compared to the wild-type strain, a mutant of pneumococcus with the cbpE gene deleted (i) displays a reduced level of plasminogen binding and plasmin activation and (ii) shows reduced ability to cross the extracellular matrix in an in vitro model. These results support the idea of a physiological role for the CBPE-plasminogen interaction in pneumococcal dissemination into human tissue.

Plasminogen- and Fibronectin-binding Protein B Is Involved in the Adherence of Streptococcus pneumoniae to Human Epithelial Cells

“…Moreover, PfbB appeared to significantly contribute to the ability of whole bacteria to bind plasminogen, as shown by experiments using a pfbB-deleted mutant. Such ability is considered an important virulence factor because, by this mechanism, pneumococci may acquire potent proteolytic activity, which would enable them to degrade the extracellular matrix and fibrin and thereby to disseminate within the body (4,23,24). It was recently proposed that pneumococci covered with active plasmin degrade intercellular junction proteins and migrate, by this process, through epithelial barriers using a pericellular route (24).…”

“…It was recently proposed that pneumococci covered with active plasmin degrade intercellular junction proteins and migrate, by this process, through epithelial barriers using a pericellular route (24). Moreover, plasminogen could promote pneumococcal adherence to epithelial cells, because this protein is present not only in plasma but also (albeit at considerably lower concentrations) in bronchoalveolar fluid, from which it could be captured by pneumococci and used to interact with the plasminogen receptors expressed by epithelial cells (24). Further studies are underway to evaluate this possibility.…”

“…Such ability is considered an important virulence factor because, by this mechanism, pneumococci may acquire potent proteolytic activity, which would enable them to degrade the extracellular matrix and fibrin and thereby to disseminate within the body (4,23,24). It was recently proposed that pneumococci covered with active plasmin degrade intercellular junction proteins and migrate, by this process, through epithelial barriers using a pericellular route (24). Moreover, plasminogen could promote pneumococcal adherence to epithelial cells, because this protein is present not only in plasma but also (albeit at considerably lower concentrations) in bronchoalveolar fluid, from which it could be captured by pneumococci and used to interact with the plasminogen receptors expressed by epithelial cells (24).…”

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

“…When activated by endogenous activators like tissue-type plasminogen activator or urokinasetype plasminogen activator (uPA), the protease plasmin degrades ECM components like fibrinogen, fibronectin, vitronectin, and laminin and regulates cell migration, coagulation, fibrinolysis, inflammation, wound healing, and tissue remodeling (18,19). Plasminogen is acquired by several pathogens, including P. aeruginosa, Streptococcus pneumoniae, Borrelia burgdorferi, Staphylococcus aureus, Lactobacillus johnsonii, and Candida albicans for ECM interaction, and activated plasmin is then used for destruction of host basement membranes and ECM (11,(20)(21)(22)(23).…”

Review: Current and new generation pneumococcal vaccines

“…91 Plasminogen is also located on the surface of various types of host cell, including epithelial and endothelial cells.…”