Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Infection.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsMartins Gomes, Sara F
Westermann, Alexander J
Förstner, Konrad U
Shusta, Eric V
Kim, Brandon J
MetadataShow full item record
AbstractMeningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs.
CitationFront Microbiol. 2019 May 29;10:1181. doi: 10.3389/fmicb.2019.01181. eCollection 2019.
AffiliationHIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.
JournalFrontiers in Microbiology
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- Neisseria meningitidis Infection of Induced Pluripotent Stem-Cell Derived Brain Endothelial Cells.
- Authors: Endres LM, Schubert-Unkmeir A, Kim BJ
- Issue date: 2020 Jul 14
- Modeling Group B <i>Streptococcus</i> and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells.
- Authors: Kim BJ, Bee OB, McDonagh MA, Stebbins MJ, Palecek SP, Doran KS, Shusta EV
- Issue date: 2017 Nov-Dec
- In Vitro Models for Studying the Interaction of Neisseria meningitidis with Human Brain Endothelial Cells.
- Authors: Kim BJ, Schubert-Unkmeir A
- Issue date: 2019
- Development of Human in vitro Brain-blood Barrier Model from Induced Pluripotent Stem Cell-derived Endothelial Cells to Predict the in vivo Permeability of Drugs.
- Authors: Li Y, Sun X, Liu H, Huang L, Meng G, Ding Y, Su W, Lu J, Gong S, Terstappen GC, Zhang R, Zhang W
- Issue date: 2019 Dec
- Accelerated differentiation of human induced pluripotent stem cells to blood-brain barrier endothelial cells.
- Authors: Hollmann EK, Bailey AK, Potharazu AV, Neely MD, Bowman AB, Lippmann ES
- Issue date: 2017 Apr 13