Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells

ABSTRACT Bacterial meningitis is a serious infection of the central nervous system (CNS) that occurs after bacteria interact with and penetrate the blood-brain barrier (BBB). The BBB is comprised of highly specialized brain microvascular endothelial cells (BMECs) that function to separate the circul...

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Autores principales:	Brandon J. Kim, Olivia B. Bee, Maura A. McDonagh, Matthew J. Stebbins, Sean P. Palecek, Kelly S. Doran, Eric V. Shusta
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	blood-brain barrier group B Streptococcus stem cells Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/59296184a85c450980a4dc35131fedb2
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spelling	oai:doaj.org-article:59296184a85c450980a4dc35131fedb22021-11-15T15:21:52ZModeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells10.1128/mSphere.00398-172379-5042https://doaj.org/article/59296184a85c450980a4dc35131fedb22017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00398-17https://doaj.org/toc/2379-5042ABSTRACT Bacterial meningitis is a serious infection of the central nervous system (CNS) that occurs after bacteria interact with and penetrate the blood-brain barrier (BBB). The BBB is comprised of highly specialized brain microvascular endothelial cells (BMECs) that function to separate the circulation from the CNS and act as a formidable barrier for toxins and pathogens. Certain bacteria, such as Streptococcus agalactiae (group B Streptococcus [GBS]), possess the ability to interact with and penetrate the BBB to cause meningitis. Modeling bacterial interaction with the BBB in vitro has been limited to primary and immortalized BMEC culture. While useful, these cells often do not retain BBB-like properties, and human primary cells have limited availability. Recently, a human induced pluripotent stem cell (iPSC)-derived BMEC model has been established that is readily renewable and retains key BBB phenotypes. Here, we sought to evaluate whether the iPSC-derived BMECs were appropriate for modeling bacterial interaction with the BBB. Using GBS as a model meningeal pathogen, we demonstrate that wild-type GBS adhered to, invaded, and activated the iPSC-derived BMECs, while GBS mutants known to have diminished BBB interaction were attenuated in the iPSC-derived model. Furthermore, bacterial infection resulted in the disruption of tight junction components ZO-1, occludin, and claudin-5. Thus, we show for the first time that the iPSC-derived BBB model can be utilized to study BBB interaction with a bacterial CNS pathogen. IMPORTANCE Here for the first time, human iPSC-derived BMECs were used to model bacterial interaction with the BBB. Unlike models previously used to study these interactions, iPSC-derived BMECs possess robust BBB properties, such as the expression of complex tight junctions that are key components for the investigation of bacterial effects on the BBB. Here, we demonstrated that GBS interacts with the iPSC-derived BMECs and specifically disrupts these tight junctions. Thus, using this BBB model may allow researchers to uncover novel mechanisms of BBB disruption during meningitis that are inaccessible to immortalized or primary cell models that lack substantial tight junctions.Brandon J. KimOlivia B. BeeMaura A. McDonaghMatthew J. StebbinsSean P. PalecekKelly S. DoranEric V. ShustaAmerican Society for Microbiologyarticleblood-brain barriergroup B Streptococcusstem cellsMicrobiologyQR1-502ENmSphere, Vol 2, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	blood-brain barrier group B Streptococcus stem cells Microbiology QR1-502
spellingShingle	blood-brain barrier group B Streptococcus stem cells Microbiology QR1-502 Brandon J. Kim Olivia B. Bee Maura A. McDonagh Matthew J. Stebbins Sean P. Palecek Kelly S. Doran Eric V. Shusta Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
description	ABSTRACT Bacterial meningitis is a serious infection of the central nervous system (CNS) that occurs after bacteria interact with and penetrate the blood-brain barrier (BBB). The BBB is comprised of highly specialized brain microvascular endothelial cells (BMECs) that function to separate the circulation from the CNS and act as a formidable barrier for toxins and pathogens. Certain bacteria, such as Streptococcus agalactiae (group B Streptococcus [GBS]), possess the ability to interact with and penetrate the BBB to cause meningitis. Modeling bacterial interaction with the BBB in vitro has been limited to primary and immortalized BMEC culture. While useful, these cells often do not retain BBB-like properties, and human primary cells have limited availability. Recently, a human induced pluripotent stem cell (iPSC)-derived BMEC model has been established that is readily renewable and retains key BBB phenotypes. Here, we sought to evaluate whether the iPSC-derived BMECs were appropriate for modeling bacterial interaction with the BBB. Using GBS as a model meningeal pathogen, we demonstrate that wild-type GBS adhered to, invaded, and activated the iPSC-derived BMECs, while GBS mutants known to have diminished BBB interaction were attenuated in the iPSC-derived model. Furthermore, bacterial infection resulted in the disruption of tight junction components ZO-1, occludin, and claudin-5. Thus, we show for the first time that the iPSC-derived BBB model can be utilized to study BBB interaction with a bacterial CNS pathogen. IMPORTANCE Here for the first time, human iPSC-derived BMECs were used to model bacterial interaction with the BBB. Unlike models previously used to study these interactions, iPSC-derived BMECs possess robust BBB properties, such as the expression of complex tight junctions that are key components for the investigation of bacterial effects on the BBB. Here, we demonstrated that GBS interacts with the iPSC-derived BMECs and specifically disrupts these tight junctions. Thus, using this BBB model may allow researchers to uncover novel mechanisms of BBB disruption during meningitis that are inaccessible to immortalized or primary cell models that lack substantial tight junctions.
format	article
author	Brandon J. Kim Olivia B. Bee Maura A. McDonagh Matthew J. Stebbins Sean P. Palecek Kelly S. Doran Eric V. Shusta
author_facet	Brandon J. Kim Olivia B. Bee Maura A. McDonagh Matthew J. Stebbins Sean P. Palecek Kelly S. Doran Eric V. Shusta
author_sort	Brandon J. Kim
title	Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
title_short	Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
title_full	Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
title_fullStr	Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
title_full_unstemmed	Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells
title_sort	modeling group b <italic toggle="yes">streptococcus</italic> and blood-brain barrier interaction by using induced pluripotent stem cell-derived brain endothelial cells
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/59296184a85c450980a4dc35131fedb2
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Modeling Group B <italic toggle="yes">Streptococcus</italic> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells

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