Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR

Ningyu Zhu; Chengxian Zhang; Atish Prakash; Zheng Hou; Wei Liu; Weifeng She; Andrew Morris; Kwang Sik Kim

doi:10.15252/emmm.202012651

Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR

Ningyu Zhu, Chengxian Zhang, Atish Prakash, Zheng Hou, Wei Liu, Weifeng She, Andrew Morris, Kwang Sik Kim

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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
Article number	e12651
Journal	EMBO Molecular Medicine
Volume	13
Issue number	3
DOIs	https://doi.org/10.15252/emmm.202012651
State	Published - Mar 5 2021

Bibliographical note

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

Funding

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. −/− −/−

Funders	Funder number
US National Institutes for Health
National Institutes of Health (NIH)	AI84984, AI113273, AI126176
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS091102

Keywords

CysLTs
EGFR
GBS meningitis
S1P
blood–brain barrier

ASJC Scopus subject areas

Molecular Medicine

Access to Document

10.15252/emmm.202012651

Cite this

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title = "Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR",

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.",

keywords = "CysLTs, EGFR, GBS meningitis, S1P, blood–brain barrier",

author = "Ningyu Zhu and Chengxian Zhang and Atish Prakash and Zheng Hou and Wei Liu and Weifeng She and Andrew Morris and \{Sik Kim\}, Kwang",

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AU - Zhu, Ningyu

AU - Zhang, Chengxian

AU - Prakash, Atish

AU - Hou, Zheng

AU - Liu, Wei

AU - She, Weifeng

AU - Morris, Andrew

AU - Sik Kim, Kwang

PY - 2021/3/5

Y1 - 2021/3/5

N2 - 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.

AB - 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.

KW - CysLTs

KW - EGFR

KW - GBS meningitis

KW - S1P

KW - blood–brain barrier

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VL - 13

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 3

M1 - e12651

ER -

Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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Cite this