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

Germana Lentini,Carmelo Biondo,Arnaud Firon,Giuseppe Teti,Concetta Beninati,Emanuela Mazzon,Patrick Trieu-Cuot,Letizia Romeo,Roberta Galbo,Angelina Midiri,Giuseppe Mancuso,Annamaria Passantino

doi:10.1038/s41598-018-32774-8

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.

Highlights

Streptococcus agalactiae, is a Gram-positive encapsulated bacterium that is frequently found as a commensal in the human gastrointestinal and genital tracts[1,2]
In contrast to CC23 strains, the protein is expressed at very low levels on the surface of CC17 strains grown under standard laboratory conditions[34], which may greatly limit the potential usefulness of PbsP in an anti-GBS vaccine[34]
Survival was increased in mice infected with the ∆pbsP mutant and, at the end of the experiment, only 2 out of 16 (12%) of the mice infected with the mutant strain died, while 10 out of 16 (62%) of those challenged with the wild type (WT) strain succumbed to infection (Fig. 1B)

Summary

Introduction

Streptococcus agalactiae ( referred to as Group B Streptococcus or GBS), is a Gram-positive encapsulated bacterium that is frequently found as a commensal in the human gastrointestinal and genital tracts[1,2]. We recently characterized PbsP (Plasminogen binding surface Protein), a cell wall-anchored protein that is required for acquisition of surface-associated Pln activity by GBS and for its dissemination from the blood to the brain[34]. This protein is a valuable vaccine candidate since PbsP is highly conserved (>99.3% identity at the protein level) and the pbsP gene is present in all sequenced human GBS strains. In contrast to CC23 strains, the protein is expressed at very low levels on the surface of CC17 strains grown under standard laboratory conditions[34], which may greatly limit the potential usefulness of PbsP in an anti-GBS vaccine[34]

Methods

Results

Conclusion