piwik-script

Deutsch Intern
    Institut für Hygiene und Mikrobiologie

    Meningeal blood-CSF barrier model



    Neisseria meningitidis (Nm, meningococcus) is a human-specific pathogen that can interact with and penetrate brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier (mBCSFB), and cause meningitis. The human-specific nature of Nm has presented unique challenges in modeling this complex host-pathogen interaction. Although research conducted on BECs alone has identified important virulence factors, the mechanisms that govern meningococcal penetration of BECs and subsequent interaction with leptomeningeal cells (LMCs) are still not fully understood.

    Here we utilize two prominent model BECs – the immortalized cell line hCMEC/D3 and a recently established model that derives BECs from induced pluripotent stem cells (iPSC) sources – and meningioma-derived LMCs to develop a more complex in vitro model of the mBCSFB and investigate the mechanisms of Nm invasion and subsequent meningeal infection. We have previously used the novel iPSC-derived BEC-like cells as a model to study bacterial interaction with the BEC barrier (Endres et al, 2020; Kim et al, 2019; Martins-Gomes et al, 2019).

    Funding and Collaboration

    This project currently receives funding from the DFG as part of the Research Training Group (Graduiertenkolleg) GRK 2157 (Project 04), which aims to develop and utilize complex 3D models to elucidate host-pathogen interaction mechanisms of human-specific pathogens in vitro.

    Aside from the supportive network of the GRK2157, we currently work in close collaboration with Prof. Christian Stigloher  (Biocenter, Core Imaging Facility), Prof. Myron Christodoulides (University of Southampton; meningioma derived LMCs), and Prof. Eric Shusta (University of Wisconsin-Madison) and Brandon Kim (University of Alabama; iPSC-derived BEC model and bacterial interaction).


    New Funding - 2020-2025

    GRK 2157 Research Training Group "3D tissue models for the investigation of microbial infections by human pathogens"

    Project 04: “Development of a multi-cell in vitro model of the meningeal blood-cerebrospinal fluid barrier to study Neisseria meningitidis infection”

    Funding – 2016-2020

    GRK 2157 Research Training Group "3D tissue models for the investigation of microbial infections by human pathogens"

    Project 04: “Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection”



    References

    Endres, L. M., Schubert-Unkmeir, A., Kim, B. J. Neisseria meningitidis Infection of Induced Pluripotent Stem-Cell Derived Brain Endothelial Cells. J. Vis. Exp. (161), e61400, doi:10.3791/61400 (2020).

    Kim BJ, McDonagh MA, Deng L, et al. Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells. Fluids Barriers CNS. 2019;16(1):26. Published 2019 Aug 22. doi:10.1186/s12987-019-0146-5

    Martins Gomes SF, Westermann AJ, Sauerwein T, Hertlein T, Förstner KU, Ohlsen K, Metzger M, Shusta EV, Kim BJ, Appelt-Menzel A, Schubert-Unkmeir A. Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection. Front Microbiol. 2019 May 29;10:1181

    Kim BJ, Schubert-Unkmeir A. In Vitro Models for Studying the Interaction of Neisseria meningitidis with Human Brain Endothelial Cells. Methods Mol Biol. 2019; 1969:135-148.

    Doran KS, Fulde M, Gratz N, Kim BJ, Nau R, Prasadarao N, Schubert-Unkmeir A, Tuomanen EI, Valentin-Weigand P. Host-pathogen interactions in bacterial meningitis. Acta Neuropathol. 2016 Feb;131(2):185-209.