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Streptococcus agalactiae (Group B Streptococcus [GBS]) is an opportunistic pathogen that normally colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, GBS can cause severe disease when transmitted to newborns. Despite widespread antibiotic prophylaxis administration to colonized mothers, GBS remains a leading cause of neonatal meningitis. Bacterial meningitis is a life-threatening infection of the central nervous system (CNS) and is marked by GBS gaining access to the blood and further by penetration of GBS across the blood-brain barrier (BBB) and activation of host inflammatory responses. Although several GBS surface proteins have been shown to impact bacterial adhesion to endothelium, a direct interaction between a GBS factor and a host endothelial ligand had not been described. Additionally, while it is known that the bacterium tightly regulates its expression of virulence factors in order to occupy various host niches, there are currently many uncharacterized GBS transcriptional regulators. Also, GBS likely competes or cooperates with other resident microbes in the vaginal tract during colonization, however little work has been done to model polymicrobial interactions within this host niche. For this PhD dissertation, I investigated how this bacterium is able to persist in the vagina, transition to an invasive pathogen, disrupt host barriers, and ultimately penetrate into the brain to cause meningitis. I examined a GBS adhesin which promoted bacterial attachment to the brain endothelium and discovered the endothelial receptor for this GBS factor. I also characterized a GBS transcriptional regulator that influenced meningitis as well as GBS vaginal carriage by impacting host immune signaling. Lastly, I developed an in vivo vaginal colonization model for another common opportunistic pathogen, Staphylococcus aureus, which likely interacts with GBS within this host niche. Using this model, I showed that bacterial interactions with fibrinogen as well as iron uptake are key determinants of vaginal persistence. Taken together, this dissertation furthers our understanding of how GBS adapts to different host niches in order to transition from asymptomatic colonization to causing invasive inflammatory disease and provides novel insights into GBS disease pathogenesis and treatment strategies to prevent colonization and invasive CNS disease.