PbsP, a cell wall‐anchored protein that binds plasminogen to promote hematogenous dissemination of group B Streptococcus

Abstract

Streptococcus agalactiae (Group B Streptococcus or GBS) is a leading cause of invasive infections in neonates whose virulence is dependent on its ability to interact with cells and host components. We here characterized a surface protein with a critical function in GBS pathophysiology. This adhesin, designated PbsP, possesses two Streptococcal Surface Repeat domains, a methionine and lysine-rich region, and a LPXTG cell wall-anchoring motif. PbsP mediates plasminogen (Plg) binding both in vitro and in vivo and we showed that cell surface-bound Plg can be activated into plasmin by tissue plasminogen activator to increase the bacterial extracellular proteolytic activity. Absence of PbsP results in a decreased bacterial transmigration across brain endothelial cells and impaired virulence in a murine model of infection. PbsP is conserved among the main GBS lineages and is a major plasminogen adhesin in non-CC17 GBS strains. Importantly, immunization of mice with recombinant PbsP confers protective immunity. Our results indicate that GBS have evolved different strategies to recruit Plg which indicates that the ability to acquire cell surface proteolytic activity is essential for the invasiveness of this bacterium.

TheStreptococcus agalactiaecell wall‐anchored protein PbsP mediates adhesion to and invasion of epithelial cells by exploiting the host vitronectin/αvintegrin axis

“…Our data show that the PbsP cell wall protein, which was previously found to mediate plasmin‐dependent invasion of endothelial barriers (Buscetta et al, ), also promotes Vtn‐dependent bacterial adhesion and invasion of epithelial cells. This indicates that PbsP is a multi‐ligand protein capable of hijacking, either at the same or at different times during pathogenesis, at least two major components of the host ECM.…”

“…Collectively these data indicate that PbsP strongly binds to the surface of human epithelial cells through its SSURE domains. This property is apparently unrelated to the previously reported ability of PbsP to bind plasminogen, which resides predominantly in the MK-rich region of the protein (Buscetta et al, 2016).…”

“…Cremoris MG1363 strain (Mancuso et al, 2009). The mutant ΔpbsP strain used here was obtained from GBS strain BM110, as previously described (Buscetta et al, 2016). All GBS strains were grown at 37°C in Todd-Hewitt broth or Todd-Hewitt agar (both from Difco Laboratories).…”

“…PbsP (Plasminogen binding surface Protein) is a recently identified cell wall protein and virulence factor of GBS containing a novel plasminogen‐binding domain (defined as the MK‐rich region) and one or two repeated Streptococcal Surface Repeat (SSURE) domains, which are homologous to domains found in other streptococcal species (Bumbaca et al, ; Buscetta et al, ). PbsP differs from most of the ECM‐binding proteins described thus far for its high degree of conservation among human GBS isolates and for being positively regulated to a remarkable extent both in vivo , during experimental infection, and in vitro , upon contact with human cells.…”

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

“…aureus, like other invasive pathogens such as S. pneumoniae (13,14), S. pyogenes (15,16), and S. agalactiae (17,34,35) can capture PLG from human plasma. Staphylococcal proteins that bind the human protein have been described previously, the secreted and wall-associated protein Sbi (29), the MntC (30), and the moonlighting cytoplasmic protein enolase (31), but the biological significance of these interactions is not clear because experiments were performed either with purified protein in vitro or with cell lysates.…”