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.
Original language | English |
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Article number | e12651 |
Journal | EMBO Molecular Medicine |
Volume | 13 |
Issue number | 3 |
DOIs | |
State | Published - Mar 5 2021 |
Bibliographical note
Funding Information:We thank D. Pearce for technical assistance in experiments with HBMECs, Vincent Bruno for RNA‐seq experiments, and K. Frank Austen and Yoshihide Kanaoka for providing CysLT1 and CysLT2 mice. This work was supported by the US National Institutes of Health (NIH) grants, NS091102, AI84984, AI113273, and AI126176 to KSK. −/− −/−
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
Keywords
- CysLTs
- EGFR
- GBS meningitis
- S1P
- blood–brain barrier
ASJC Scopus subject areas
- Molecular Medicine