Modeling Group B Streptococcus and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells

Abstract

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.

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.