Analyzing Group B Streptococcal and Host Factors Influencing Vaginal Colonization and Exploring Therapeutic Interventions.

摘要

Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive bacterium which colonizes the cervicovaginal tract in 20-30% of healthy women. Colonization is asymptomatic; however, during pregnancy, GBS can cause several complications such as chorioamnionitis and urinary tract infections, or alternatively, can be vertically transmitted to newborns peripartum causing pneumonia, sepsis or meningitis. Current prophylaxis, consisting of late gestation screening and intrapartum antibiotics, has failed to completely prevent transmission, and GBS remains the leading cause of bacterial neonatal meningitis in the United States. Unfortunately, little is known about the host and bacterial factors that promote or permit GBS vaginal colonization. For this PhD dissertation project, I examined the host innate and adaptive immune responses during GBS vaginal colonization and identified several key bacterial factors, such as toxin production and strain differences, that elicited a strong immune response or altered persistence in the vaginal tract. This was accomplished using immortalized human cervical and vaginal cell lines in vitro, as well as utilizing an established mouse model of GBS vaginal colonization. Secondly, I identified GBS factors that contribute to successful vaginal colonization, including determinates controlling interactions with host tissues and other normal flora. GBS has multiple two component regulatory systems that have been previously shown to regulate bacterial gene expression, some of which control factors that promote host cell adherence and production of a putative bacteriocin-like inhibitory substance (BLIS). I utilized molecular techniques to both study contributions of specific two component systems to vaginal colonization as well as confirmed BLIS activity. Lastly, I explored therapeutic intervention strategies to remove GBS from the vaginal tract including treatment with a novel immunostimulatory peptide or administration of a probiotic microbe to limit GBS vaginal colonization. Altogether, this dissertation furthered our understanding of the GBS-host interaction within the vaginal environment, which will lead to potential therapeutic targets to control maternal vaginal colonization during pregnancy and prevent transmission to the vulnerable newborn.