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New models of Streptococcal disease for investigating bacterial and host factors involved in bacterial penetration of the blood-brain barrier


Bacterial meningitis is a serious and life threatening disease caused by infection of the meningeal tissue surrounding the brain. Bacterial infection leads to a sustained pro-inflammatory response and the corresponding infiltration of the by dendritic cells can damage the tissue. Before bacteria can penetrate into the central nervous system they must first persist in the blood long enough to interact and cross with the blood-brain-barrier (BBB). To study the complex interactions between host and microbe that occur during bacterial meningitis we utilize the model organism Group B Streptococcus (GBS). GBS is the causative organism of neonatal meningitis. During pregnancy neonates can become infected with GBS through vertical transmission either in utero or during the process of birth. Current treatment of GBS disease relies on prophylactic antibiotics as there is no vaccine available. Little is known about the underlying mechanisms that lead to GBS disease progression and meningitis. For this dissertation I worked to adapt larval zebrafish into an in vivo model of GBS infection to better understand host-pathogen factors that contribute to disease. I helped to identify a novel mechanism by which GBS activation of a specific transcription factor leads to BBB dysfunction, further I sought to identify which bacterial proteins contribute to this mechanism and in doing so I have identified a candidate series of proteins. Lastly I investigated and characterized new commercially available immortalized human cell line for its usage to model GBS disease in vitro. Overall my dissertation research has increased our understanding of the mechanisms underlying BBB disruption during GBS infection, potential GBS proteins implicated in this phenomenon, and new models to study streptococcal disease.

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