Megan Branum

Background: Neonatal invasive GBS disease is the leading cause of infection-related neonatal morbidity and mortality globally, caused by the bacterium Streptococcus agalactiae, colloquially known as Group-B Streptococcus (GBS).^1-4  After transmission from asymptomatically colonized genitourinary tracts of pregnant women, GBS utilizes virulence factors for pathogenic invasion of neonates.^1-4 Current antibiotic prophylaxis decreases incidence and fatality of early onset of disease (EOD) manifestations characterized by septicemia and pneumonia but are insufficient in preventing late onset of disease (LOD) manifestations characterized by bacteremia without foci and meningitis, which are on the rise globally.³ The molecular mechanisms dictating GBS pathogenicity require elucidation in order to develop new therapeutic strategies for both manifestations, particularly before predicted future emergence of phenotypic antimicrobial resistance.⁴ Recent studies have characterized the GBS virulence factor plasminogen-binding protein (PbsP) as a cell-wall anchored protein with a highly conserved gene sequence and expressed at varying levels across common invasive GBS strains.^6,9 Thus, PbsP may be a promising therapeutic target if its role in pathogenesis of invasive GBS disease is understood.

Objective: In this narrative review, we explored the role of PbsP in the pathogenesis of invasive GBS meningitis and its viability as a therapeutic target.

Search Methods: An online search in the PubMed Database was conducted from 2016-2023 using the following keywords: “Group B Streptococcus”, “plasminogen binding protein”, “PbsP”, “CC17”.

Results: Studies indicate that some invasive strains display low PbsP expression in vitro, but pbsP transcription was upregulated in vivo during vaginal colonization and when contact was made with brain microvascular endothelial cells.^5,8,9 PbsP binds two host ECM components, plasminogen (Plg) and vitronectin (Vtn).^6,7,9 PbsP-Vtn binding was demonstrated across common invasive strains, mediated by PbsP SSURE domains interacting with Vtn heparin-binding sites.⁶ Epithelial cell adherence and invasion, mediated by PbsP-Vtn binding, was significantly reduced in ΔpbsP mutant.⁶ Studies indicate that the MK-rich domain of PbsP, possibly in cooperation with SSURE domains, bind the Plg Kringle 4 domain.^7,9 ΔpbsP mutant adherence to human brain endothelium and invasion/transmigration across endothelial barriers in vitro and the CNS in vivo was significantly reduced.^8,9 Selective hematogenous spread to the CNS demonstrated in these studies required host tissue plasminogen activator, suggested to function in converting PbsP-bound Plg to PbsP-bound plasmin resulting in proteolytic degradation of the blood-brain barrier.⁹ Significant neuroprotection in the form of reduced bacterial colony counts in the brain, lower inflammatory markers, and diminished occurrence of lethality and encephalitis was induced with anti-PbsP vaccination.^8,9

Conclusions: Studies demonstrate that PbsP binding of vitronectin and plasminogen may result in dual function of PbsP as a virulence factor contributing to maintenance of maternal vaginal colonization and selective hematogenous spread to the CNS. Further consideration of the pathogenic role of PbsP as a virulence factor, which is widely conserved and expressed among invasive strains, could lead to more effective therapeutic strategies against invasive GBS disease and the rising number of LOD meningitis manifestations.

Works Cited:

1. Armistead B, Oler E, Waldorf KA, Lakshmi R. The double life of Group B Streptococcus: Asymptomatic colonizer and potent pathogen. J Mol Bio. 2019;431(16):2914-2931.
2. Pietrocola G, Arciola CR, Rindi S, Montanaro L, Speziale P. Streptococcus agalactiae non-pilus, cell wall-anchored proteins: Involvement in colonization and pathogenesis and potential as vaccine candidates. Front. Immunol. 2018;9:602.
3. Tavares T, Pinho L, Andrade EB. Group B Streptococcal neonatal meningitis. Clin. Microbiol. Rev. 2022;35(2):e00079-21.
4.  Zhou Y, Wang L, Yan Q, Lee C, Hsu M, Zhang L, Chiu C. Genomic analysis of Group B Streptococcus from neonatal sepsis reveals clonal CC17 expansion and virulence- and resistance-associated traits after intrapartum antibiotic prophylaxis. Clin. Infect. Dis. 2022; 75(12):2153-2160.
5. Cook LCC, Hu H, Maienschein-Cline M, Federle MJ. A vaginal tract signal detected by Group B Streptococcus SaeRS system elicits transcriptomic changes and enhances murine colonization. Infect. Immun. 2018; 86(4):e00762-17.
6. Valerio de Gaetano G, Pietrocola G, Romeo L, Galbo R, Lentini G, Giardina M, Biondo C, Midiri A, Mancuso G, Venza M, Venza I, Firon A, Trieu-Cuot P, Teti G, Speziale P, Beninati C. The Streptococcus agalactiae cell wall-anchored protein PbsP mediates adhesion to and invasion of epithelial cells by exploiting the host vitronectin/ɑ_v integrin axis. Mol. Microbio. 2018; 110(1):82-94.
7. Coppolino F, Romeo L, Pietrocola G, Lentini G, Valerio De Gaetano G, Teti G, Galbo R, Beninati C. Lysine residue in the MK-rich region are not required for binding of the PbsP protein from Group B Streptococci to plasminogen. Front. Cell. Infect. Microbio. 2021; 11:679792.
8. Lentini G, Midiri A, Firon A, Galbo R, Mancuso G, Biondo C, Mazzon E, Passantino A, Romeo L, Trieu-Cuot P, Teti G, Beninati C. The plasminogen binding protein PbsP is required for brain invasion by hypervirulent CC17 group B streptococci. Sci. Rep. 2018;8:14322
9. Buscetta M, Firon A, Pietrocola G, Biondo C, Mancuso G, Midiri A, Romeo L, Galbo R, Venza M, Venza I, Kaminski PA, Gominet M, Teti G, Speziale P, Trieu-Cuot P, Beninati C. PbsP, a cell-wall anchored protein that binds plasminogen to promote hematogenous dissemination of group B Streptococcus. Mol. Microbio. 2016;101(1):27-41.