Angela Vong

Introduction. Neonatal meningitis is an inflammation of the meninges due to an infectious agent. The leading causative pathogen is Group B Streptococcus (GBS), a commensal but opportunistic gram-positive bacterium.¹ GBS has asymptomatically colonized the vaginal epithelium of 20% of women worldwide.¹ Transmission to the neonate can be through ascending infection or through vertical transmission with a mortality rate of 10% and up to 50% of survivors will develop congenital defects or neurological impairments.^{1, 2, 3, 5} Out of the different GBS serotypes, hypervirulent CC17-GBS is the most invasive.^{1, 4, 6} Despite CC17-GBS accounting for more than 70% of neonatal meningitis cases, there are no available vaccines.¹ Based on current research, the Srr2, BspC, and PbsP surface adhesins could be potential therapeutic targets to reduce infections. Methods. Non-CC17-GBS Srr1 and CC17-GBS exclusive Srr2 were compared using sequence analysis to identify hypervirulent binding motifs.⁷ Using immunoblotting and ELISA, the affinity of the isolated motifs to αvβ3 and α5β1 human integrins were analyzed.⁷ For BspC, 2D electrophoresis and mass spectrometry were used to determine the host receptor.⁸ ΔbspC mutant was compared to WT GBS in mice models and the brain bacterial load was analyzed.⁸ For PbsP, ELISA and plasminogen fragment probes were used to identify binding regions.⁹ ΔPbsP mutant was compared to WT CC17-GBS in mice models with a quantitative RT-PCR analysis of bacterial RNA found in the brain tissue.⁹ Results. The hypervirulent binding motifs of the Srr2 fibrinogen-binding region are SVD and RGD.⁷ αvβ3 required both SVD and RGD, but α5β1 instead required the FVSKI motif.⁷ BspC interacts with vimentin and ΔbspC led to decreased brain tissue infiltration.⁸ PbsP-plasminogen binding is due to the MK-rich domain and Kringle 4.^{9, 10} ΔPbsP is less lethal with decreased brain bacterial load in comparison to WT.⁹ PbsP mRNA levels were upregulated in vivo after contact with brain endothelial cells.⁹ Conclusions. Srr2 attaches to fibrinogen by recognizing αvβ3 and α5β1 integrins; BspC attaches to vimentin; and PbsP attaches to plasminogen using the MK-rich and Kringle 4 domains to hijack the fibrinolytic system and break down the extracellular matrix of endothelial cells. Any downregulation or blockade of these adhesins resulted in diminished hyperadhesion and penetration of the blood-brain barrier. Therefore, Srr2, BspC, and PbsP are necessary for pathogenesis and make viable therapeutic targets for preventative strategies. With further mechanistic research and development of models that can mimic the natural human infectious process, a universal GBS vaccine may be created.

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