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.
Highlights
The blood–brain barrier (BBB) and other brain barriers such as the meningeal blood-cerebrospinal fluid barrier are comprised of highly specialized brain endothelial cells (BECs) that promote proper brain function by separating the circulation from the central nervous system (CNS) [1,2,3]
Using a substrate accumulation assay and consistent with prior observations, BECs treated with the P-gp inhibitor Cyclosporine A (CsA) accumulated more of the P-gp substrate Rhodamine 123 (R123) than non-CsA-treated cells, indicating that P-gp is active in these BECs
Following Group B Streptococcus (GBS) infection, we observed a significant increase of R123 accumulation in BECs when compared to uninfected BECs, to levels matching those with CsA inhibition (Fig. 1a)
Summary
The blood–brain barrier (BBB) and other brain barriers such as the meningeal blood-cerebrospinal fluid barrier are comprised of highly specialized brain endothelial cells (BECs) that promote proper brain function by separating the circulation from the central nervous system (CNS) [1,2,3]. BECs possess unique phenotypes that include the presence of specialized efflux transporters, complex tight junctions, and low rates of endocytosis [1,2,3]. Together, these properties maintain brain homeostasis and help to prevent the entry of pathogens and toxins into the CNS. GBS disruption of the BECs and other brain barriers during meningitis has been documented, Kim et al Fluids Barriers CNS (2019) 16:26 and it has been shown that tight junctions are disrupted and endocytosis pathways altered [19, 20]. We show that bacterial infection can alter P-gp function in BECs, suggesting another mechanism by which bacterial pathogens contribute to BEC dysfunction
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