TY  - JOUR
A1  - Kim, Brandon J.
A1  - McDonagh, Maura A.
A1  - Deng, Liwen
A1  - Gastfriend, Benjamin D.
A1  - Schubert-Unkmeir, Alexandra
A1  - Doran, Kelly S.
A1  - Shusta, Eric V.
T1  - Streptococcus agalactiae disrupts P-glycoprotein function in brain endothelial cells
JF  - Fluids and Barriers of the CNS
N2  - 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.
KW  - Group B Streptococcus
KW  - Streptococcus agalactiae
KW  - Brain endothelial cells
KW  - P-glycoprotein
KW  - Efflux transport
KW  - Meningitis
KW  - Stem cells
KW  - P-gp
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201895
VL  - 16
ER  - 
TY  - JOUR
A1  - Kim, Brandon J.
A1  - Shusta, Eric V.
A1  - Doran, Kelly S.
T1  - Past and current perspectives in modeling bacteria and blood–brain barrier interactions
JF  - Frontiers in Microbiology
N2  - The central nervous system (CNS) barriers are highly specialized cellular barriers that promote brain homeostasis while restricting pathogen and toxin entry. The primary cellular constituent regulating pathogen entry in most of these brain barriers is the brain endothelial cell (BEC) that exhibits properties that allow for tight regulation of CNS entry. Bacterial meningoencephalitis is a serious infection of the CNS and occurs when bacteria can cross specialized brain barriers and cause inflammation. Models have been developed to understand the bacterial – BEC interaction that lead to pathogen crossing into the CNS, however, these have been met with challenges due to these highly specialized BEC phenotypes. This perspective provides a brief overview and outlook of the in vivo and in vitro models currently being used to study bacterial brain penetration, and opinion on improved models for the future.
KW  - bacteria
KW  - blood–brain barrier
KW  - meningitis
KW  - stem cells
KW  - brain endothelial cell
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201766
VL  - 10
IS  - 1336
ER  - 
TY  - JOUR
A1  - Doran, Kelly S.
A1  - Fulde, Marcus
A1  - Gratz, Nina
A1  - Kim, Brandon J.
A1  - Nau, Roland
A1  - Prasadarao, Nemani
A1  - Schubert-Unkmeir, Alexandra
A1  - Tuomanen, Elaine I.
A1  - Valentin-Weigand, Peter
T1  - Host-pathogen interactions in bacterial meningitis
JF  - Acta Neuropathologica
N2  - Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Pathogenesis is based on complex host-pathogen interactions, some of which are specific for certain bacteria, whereas others are shared among different pathogens. In this review, we summarize the recent progress made in understanding the molecular and cellular events involved in these interactions. We focus on selected major pathogens, Streptococcus pneumonia, S. agalactiae (Group B Streptococcus), Neisseria meningitidis, and Escherichia coli K1, and also include a neglected zoonotic pathogen, Streptococcus suis. These neuroinvasive pathogens represent common themes of host-pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood-brain and blood-cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces.
KW  - microvascular endothelial cells
KW  - outer membrane protein
KW  - Neuroinfectiology
KW  - Bacterial meningitis
KW  - Pneumococci
KW  - Meningococci
KW  - Group B Streptococcus
KW  - Streptococcus suis
KW  - Escherichia coli K1
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191034
VL  - 131
IS  - 2
ER  -