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.

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Published in EMBO Molecular Medicine, v. 13, issue 3, e12651.

© 2021 The Authors. Published under the terms of the CC BY 4.0 license

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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This work was supported by the US National Institutes of Health (NIH) grants, NS091102, AI84984, AI113273, and AI126176 to KSK.

Related Content

The datasets produced in this study are available in the following databases: RNA sequencing: NCBI sequence read archive (SRA), BioProject accession no. PRJNA632824 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA632824/).

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