Characterization of a two-component system transcriptional regulator LtdR that impacts Group B Streptococcal colonization and disease.

Streptococcus agalactiae (Group B Streptococcus , GBS) is often a commensal bacterium that colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, in immune-compromised individuals, particularly the newborn, GBS may transition to an invasive pathogen and cause serious disease. Despite currently recommended intrapartum antibiotic prophylaxis for GBS-positive mothers, GBS remains a leading cause of neonatal septicemia and meningitis. To adapt to the various host environments encountered during its disease cycle, GBS possesses multiple two-component regulatory systems (TCS). Here we investigate the contribution of a transcriptional regulator containing a LytTR domain, LtdR, to GBS pathogenesis. Disruption of the ltdR gene in the GBS chromosome resulted in a significant increase in bacterial invasion into human cerebral microvascular endothelial cells (hCMEC) in vitro as well as greater penetration of the Blood-Brain Barrier (BBB) and the development of meningitis in vivo Correspondingly, infection of hCMEC with the Δ ltdR mutant resulted in increased secretion of pro-inflammatory cytokines IL-8, CXCL-1, and IL-6. Further, using a mouse model of GBS vaginal colonization, we observed that the Δ ltdR mutant was cleared more readily from the vaginal tract and also resulted in increased cytokine production from human vaginal epithelial cells. RNA-sequencing revealed global transcriptional differences between the Δ ltdR mutant and the parental WT GBS strain. These results suggest that LtdR regulates many bacterial processes that can influence GBS-host interactions to promote both bacterial persistence and disease progression.