Bacterial and Host Determinants of Group B Streptococcal Vaginal Colonization and Ascending Infection in Pregnancy

Abstract

Group B streptococcus (GBS) is a gram-positive bacteria that asymptomatically colonizes the vaginal tract. However, during pregnancy maternal GBS colonization greatly predisposes the mother and baby to a wide range of adverse outcomes, including preterm birth (PTB), stillbirth, and neonatal infection. Although many mechanisms involved in GBS pathogenesis are partially elucidated, there is currently no approved GBS vaccine. The development of a safe and effective vaccine that can be administered during or prior to pregnancy remains a principal objective in the field, because current antibiotic-based therapeutic strategies do not eliminate all cases of invasive GBS infections. Herein, we review our understanding of GBS disease pathogenesis at the maternal-fetal interface with a focus on the bacterial virulence factors and host defenses that modulate the outcome of infection. We follow GBS along its path from an asymptomatic colonizer of the vagina to an invasive pathogen at the maternal-fetal interface, noting factors critical for vaginal colonization, ascending infection, and vertical transmission to the fetus. Finally, at each stage of infection we emphasize important host-pathogen interactions, which, if targeted therapeutically, may help to reduce the global burden of GBS.

Keywords: bacteria; colonization; fetus; group B streptococcus; placenta; pregnancy; preterm birth; vagina.

Figure 1

GBS disease manifestations for mothers and fetuses. GBS is considered a commensal colonizer of the maternal vaginal tract, but ascension of GBS into the uterus can lead to adverse perinatal outcomes. GBS can invade the amniotic cavity and fetus to cause a variety of disease manifestations in the fetus (left panel), some of which can occur even with a limited infection of the placental chorioamniotic membranes. Maternal GBS invasive disease is more infrequent and can vary in severity (right panel); more severe outcomes tend to occur in the setting of chorioamniotic membrane rupture and/or with maternal co-morbidities that compromise the immune response.

Figure 2

GBS-directed host immune responses at the maternal-fetal interface. During GBS infection at the maternal-fetal interface, a variety of immune cell interactions can occur. In the vaginal tract, epithelial cells exposed to hyperhemolytic (HH) GBS secrete C-X-C motif chemokine ligand 2 (CXCL2) and interleukin (IL)-8 which mediate GBS elimination through the recruitment of neutrophils (Patras et al., 2013). Whereas wild-type GBS colonize the lower genital tract in the presence of mast cells, HH GBS induce mast cell degranulation in a hemolysin and calcium-dependent manner. This results in the release of pre-formed mast cell mediators, such as eicosanoids and histamine that mediate GBS clearance (Gendrin et al., 2015). During ascending infection, cervical Th17 cells that produce IL-17 are associated with GBS clearance (Patras et al., 2015). Decidual stromal cells exposed to GBS produce prostaglandin E₂ (PGE₂), which suppresses macrophage tumor necrosis factor alpha (TNF-α) production (Rogers et al., 2018). Placental neutrophils produce neutrophil extracellular traps (NETs) that immobilize GBS and facilitate clearance via phagocytosis and nutritional immunity. NET-contained lactoferrin sequesters ferric iron (Fe³⁺), resulting in GBS growth arrest (Kothary et al., 2017). HH GBS evade placental NETs by hemolysin-mediated killing of neutrophils (Boldenow et al., 2016). Macrophages control placental GBS replication through a similar mechanism, and macrophage extracellular traps (METs) contain similar products (Doster et al., 2018). Finally, neutrophils in maternal and cord blood phagocytose GBS and produce reactive oxygen species (ROS) to mediate bacterial killing. However, GBS expressing hyaluronidase (HylB) inhibit this mechanism by interfering with toll-like receptor 2 and 4 signaling. Downstream effects of this immune dampening suppress ROS production and facilitate GBS survival (Coleman et al., 2021).

Figure 3

GBS exploits epithelial-mesenchymal transition (EMT) and vaginal epithelial exfoliation to permit ascending infection. During vaginal infection, GBS binds integrins on the epithelial surface and activates integrin signaling that results in the breakdown of adherens junctions. Displaced β-catenin translocates to the nucleus, activating transcriptional changes of β-catenin targets associated with EMT. Expression of these transcripts in vivo leads to vaginal epithelial exfoliation, which facilitates GBS ascension to the uterus and is associated with increased risk for microbial invasion of the amniotic cavity and preterm birth.

Figure 4

Human placental anatomy. This illustration depicts the components of the human placenta (chorionic villous tree), placental chorioamniotic membranes and the associated maternal decidua. GBS must traffic across either the decidua and chorioamniotic membranes or the chorionic villi to infect the fetus. GBS chorioamnionitis and culture-positive amniotic fluid is common in cases of fetal or neonatal invasive disease; thus, it is thought that GBS invasive disease occurs most commonly due to trafficking across the chorioamniotic membranes.