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Fluids Barriers CNS. 2019 Aug 22;16(1):26. doi: 10.1186/s12987-019-0146-5.

Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells.

Author information

1
Department of Chemical and Biological Engineering, University of Wisconsin, Madison, WI, USA. Brandon.kim@hygiene.uni-wuerzburg.de.
2
Department of Hygiene and Microbiology, University of Würzburg, Joseph Schneider Strasse 2/E1, 97080, Würzburg, Germany. Brandon.kim@hygiene.uni-wuerzburg.de.
3
Department of Chemical and Biological Engineering, University of Wisconsin, Madison, WI, USA.
4
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
5
Department of Hygiene and Microbiology, University of Würzburg, Joseph Schneider Strasse 2/E1, 97080, Würzburg, Germany.

Abstract

Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood-borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood-brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS.

KEYWORDS:

Brain endothelial cells; Efflux transport; Group B Streptococcus; Meningitis; P-glycoprotein; P-gp; Stem cells; Streptococcus agalactiae

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