TY - JOUR
T1 - Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR
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
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
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
UR - http://www.scopus.com/inward/record.url?scp=85100072270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100072270&partnerID=8YFLogxK
U2 - 10.15252/emmm.202012651
DO - 10.15252/emmm.202012651
M3 - Article
C2 - 33474818
AN - SCOPUS:85100072270
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 3
M1 - e12651
ER -