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Characterization of intracellular Group B Streptococcus and host defense
Cutting, Andrew Scott
Hampton, RandolphNizet, VictorFeuer, RalphHarris, Greg
Bacterial meningitis is a severe, life threatening concern, which results in a high proportion of patients succumbing to disease. There are limited treatments available for this disease and individuals that survive endure an immense amount of outstanding consequences for the remainder of their lives. An important causative agent of bacterial meningitis is the human pathogen Streptococcus agalactiae, also known as Group B Streptococcus (GBS). GBS is known to be the leading cause of neonatal sepsis and meningitis thereby resulting in a high incidence of mortality and morbidity. To cause meningitis, this bacterium must penetrate one of the most important barriers in the body, the blood-brain barrier (BBB). Still, the molecular mechanisms associated with the development of disease have yet to be completely described. In the past, invasive GBS was visualized within brain endothelial cells, the single cell layer that comprises the BBB, however the intracellular fate of GBS has yet to be explored. This dissertation seeks to understand the intracellular host defenses activated in response to GBS infection, the bacterial factors responsible for this activation, and the specific host and bacterial proteins that contribute to bacterial invasion and the initiation of the immune response. We explored the self-digestion pathway, known as autophagy, as playing a critical role in targeting intracellular GBS for destruction. My data suggest that while the autophagic pathway is activated in response to bacterial infection; this process is incompletely effective in eliminating the intracellular GBS. I believe that GBS can subvert autophagic recognition and subversion of this pathway may be the first step of the development of BBB disruption. Additionally, this dissertation explored canonical endocytic trafficking during GBS infection and the bacterial factors associated with differential trafficking. Finally, I have successfully identified a novel autophagy related protein responsible for bacterial uptake into brain endothelium as well as stimulation of the immune response. This protein may be a master regulator of a variety of intracellular processes and will be an interesting target for therapeutic intervention. In the end, this dissertation uncovered new information critical for understanding the intracellular potential and transcytotic nature of GBS during disease manifestation.
San Diego State University
University of California, San Diego
Doctor of Philosophy (Ph.D.) University of California, San Diego and San Diego State University, 2015
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