Abstract
Group B Streptococcus (GBS) remains the most common Gram‐positive bacterium causing neonatal meningitis and GBS meningitis continues to be an important cause of mortality and morbidity. In this study, we showed that GBS penetration into the brain occurred initially in the meningeal and cortex capillaries, and exploits a defined host cell signaling network comprised of S1P2, EGFR, and CysLT1. GBS exploitation of such network in penetration of the blood–brain barrier was demonstrated by targeting S1P2, EGFR, and CysLT1 using pharmacological inhibition, gene knockout and knockdown cells, and gene knockout animals, as well as interrogation of the network (up‐ and downstream of each other). More importantly, counteracting such targets as a therapeutic adjunct to antibiotic therapy was beneficial in improving the outcome of animals with GBS meningitis. These findings indicate that investigating GBS penetration of the blood–brain barrier provides a novel approach for therapeutic development of GBS meningitis.
Highlights
Group B Streptococcus (GBS) remains the most common Gram-positive bacterium causing neonatal meningitis and GBS meningitis continues to be an important cause of mortality and morbidity (Kim, 2008, 2010; Romain et al, 2018; O’Sullivan et al, 2019)
We showed that sphingosine 1-phosphate (S1P)-Sphingosine-1 phosphate receptor 2 (S1P2) represents upstream molecules of epidermal growth factor receptor (EGFR), while cytosolic phospholipase 2a, cysteinyl leukotrienes (CysLTs), and ezrin–radixin– moesin (ERM) represent downstream molecules of EGFR and that S1P2-EGFR-CysLTs formed a defined host cell signaling network exploited by GBS for penetration of the blood–brain barrier in vitro and in vivo
This concept was recapitulated in this study, where GBS penetration occurred initially in the meningeal and cortex capillaries, and subsequent invasion into the brain without extravasation of intravascular small molecule tracer, which was shown under a stringent condition for assessing the blood–brain barrier permeability using a small molecule of 443Da as well as without affecting structural integrity of the blood–brain barrier
Summary
Group B Streptococcus (GBS) remains the most common Gram-positive bacterium causing neonatal meningitis and GBS meningitis continues to be an important cause of mortality and morbidity (Kim, 2008, 2010; Romain et al, 2018; O’Sullivan et al, 2019). Group B Streptococcus strains are uniformly susceptible to penicillins, and poor outcome of GBS meningitis is not due to emergence of nonsusceptible GBS strains. These findings indicate new approaches are needed for development of improved therapy for GBS meningitis. Several lines of evidence from human cases and experimental animal models of GBS meningitis suggest that GBS penetration into the brain occurs in the cerebral microvessels (Berman & Banker, 1966; Ferrieri et al, 1980; Doran et al, 2005; Tazi et al, 2010), but it remains incompletely understood how GBS penetrates the blood–brain barrier. Controversy exists on whether GBS exploits transcellular and/or paracellular penetration of the blood–brain barrier (Doran et al, 2016)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
