Cellular Response of the Blood Brain Barrier to Bacterial Meningeal Pathogens
- Author(s): Kim, Brandon Jonathan
- Advisor(s): Doran, Kelly S
- et al.
Bacterial meningitis is a serious infection of the central nervous system (CNS) that if left untreated is uniformly fatal. To cause disease bacterial pathogens must survive in the blood stream, interact with and penetrate the blood brain barrier (BBB), and invoke an immune response. Streptococcus agalactiae (Group B streptococcus, GBS), is a Gram-positive non-spore forming colonizer of the human recto-vaginal tract. During pregnancy or the birthing process, GBS can be vertically transmitted to the newborn causing pneumonia, sepsis and meningitis. GBS is the leading cause of neonatal meningitis effecting up to 1000 births in the United States annually. While progress has been made in identifying bacterial factors that contribute to disease progression, little is known about the host cellular factors that are activated during infection. For this dissertation, I examine the brain endothelial cells that comprise the BBB, and their response to GBS infection. First, using an in vitro BBB model of infection, I have described a novel mechanism for GBS disruption of BBB integrity by upregulation of a transcription factor, Snail1, which inhibits tight junction expression. These findings were confirmed in an in vivo murine model of GBS meningitis, as well as in a newly developed zebrafish model. Finally, I have provided evidence that GBS is able to promote signaling in brain endothelium, by utilizing a common cellular mechanism to concentrate receptors. Taken together this dissertation has furthered our knowledge of the specific molecular mechanisms that promote BBB dysfunction during bacterial meningitis, and provide potential molecular targets for therapeutic intervention.