The plasminogen binding protein PbsP is required for brain invasion by hypervirulent CC17 Group B streptococci

Abstract

Streptococcus agalactiae (Group B Streptococcus or GBS) is a frequent cause of serious disease in newborns and adults. Epidemiological evidence indicates a strong association between GBS strains belonging to the hypervirulent CC17 clonal complex and the occurrence of meningitis in neonates. We investigate here the role of PbsP, a cell wall plasminogen binding protein, in colonization of the central nervous system by CC17 GBS. Deletion of pbsP selectively impaired the ability of the CC17 strain BM110 to colonize the mouse brain after intravenous challenge, despite its unchanged capacity to persist at high levels in the blood and to invade the kidneys. Moreover, immunization with a recombinant form of PbsP considerably reduced brain infection and lethality. In vitro, pbsP deletion markedly decreased plasmin-dependent transmigration of BM110 through brain microvascular endothelial cells. Although PbsP was modestly expressed in bacteria grown under standard laboratory conditions, pbsP expression was markedly upregulated during in vivo infection or upon contact with cultured brain endothelial cells. Collectively, our studies indicate that PbsP is a highly conserved Plg binding adhesin, which is functionally important for invasion of the central nervous system by the hypervirulent CC17 GBS. Moreover, this antigen is a promising candidate for inclusion in a universal GBS vaccine.

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

“…The integration of CovR signalling with other regulators occurs at other loci than srr2 . For instance, the PbsP adhesin encoding gene is directly activated by the SaeRS two-component system in the vagina to promote colonization (50), while pbsP transcription is also necessary at later stages of the infection process (51–53). Another example is the transcription of the gene encoding the FbsA adhesin (32) which depends on 3 additional regulators: RogB, RovS and Rgg (54–56).…”

“…The covR -synthetic DNA fragment was excised from the pEX vector by BamHI digestion and cloned into the aTc inducible expression vector pTCV_P tetO (44). The construction of the Δ covR mutants were previously reported in NEM316 (26) and BM110 (53), as well the construction of the NEM316 CovR D53A , and CovS T282A mutants obtained by precise chromosomal substitutions (26). The BM110 point mutants were constructed as described in NEM316 with the pG1 shuttle thermosensitive plasmid (26).…”

The Double Life of Group B Streptococcus: Asymptomatic Colonizer and Potent Pathogen

“…Expression of the pbsP locus is also repressed by CovR/S [81,82], but direct binding of CovR to the pbsP promoter could not be proven, suggesting that this regulation may be indirect [81]. Plasminogenbinding via PbsP also promotes invasive infection, as PbsP is required for GBS to adhere to brain endothelial cells and cross the BBB [81,83]. Additionally, PbsP confers GBS the ability to bind human vitronectin, a glycoprotein abundant in the ECM and in serum, which promotes GBS adherence to and invasion of epithelial cells [84].…”

“…Resisting macrophage and neutrophil killing [74] Disrupting barrier function of the lung and BBB [66,70,71,73] Resisting host antimicrobial peptides [74] CovR/S (PI-1) [77] Ape1 (PI-1) [77] Rga (PI-2a) [78,79] RogB (PI-2a) [66] Upstream hairpin structures (PI-2b, strain-specific) [80] PbsP Unknown, but up-regulated during vaginal colonization [24] Adhering to and invading endothelial cells that make up the BBB [81,83] CovR/S [81] SaeR/S in the vagina [24] SfbA Invading vaginal and cervical cells [85] Invading endothelial cells that make up the BBB [85] Invading astrocytes [86] Unknown BibA Binding to vaginal and cervical epithelial cells [89] Interfering with complement regulator C4bp [89] (? -not tested in vaginal model)…”

Enhanced Postnatal Acquisition of Hypervirulent Group B Streptococcus

“…Why are CC17 strains vastly overrepresented in LOD? Studies based on in vitro and animal model data suggest that the presence of the hypervirulent GBS adhesin (HvgA) may be a major factor in translocation across the gut mucosa and invasion of the blood-brain barrier, though other CC17 surface proteins and mutations in regulatory pathways may also be relevant to pathogenesis [21,23,24].…”