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.

Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated preterm labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy. IMPORTANCE Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.

Leukocyte activation within the chorioamniotic membranes is strongly associated with inflammation and preterm labor (PTL). We hypothesized that prophylaxis with a broad-spectrum chemokine inhibitor (BSCI) would downregulate the inflammatory microenvironment induced by Group B Streptococcus (GBS, Streptococcus agalactiae) to suppress PTL and microbial invasion of the amniotic cavity (MIAC). To correlate BSCI administration with PTL and MIAC, we used a unique chronically catheterized non-human primate model of Group B Streptococcus (GBS)-induced PTL. In the early third trimester (128-138 days gestation; ∼29-32 weeks human pregnancy), animals received choriodecidual inoculations of either: (1) saline (N = 6), (2) GBS, 1-5 × 10 8 colony forming units (CFU)/ml; N = 5), or (3) pre-treatment and daily infusions of a BSCI (10 mg/kg intravenous and intra-amniotic) with GBS (1-5 × 10 8 CFU/ml; N = 4). We measured amniotic cavity pressure (uterine contraction strength) and sampled amniotic fluid (AF) and maternal blood serially and cord blood at delivery. Cesarean section was performed 3 days post-inoculation or earlier for PTL. Data analysis used Fisher's exact test, Wilcoxon rank sum and one-way ANOVA with Bonferroni correction. Saline inoculation did not induce PTL or infectious sequelae. In contrast, GBS inoculation typically induced PTL (4/5, 80%), MIAC and fetal bacteremia (3/5; 60%). Remarkably, PTL did not occur in the BSCI+GBS group (0/4, 0%; p = 0.02 vs. GBS), despite MIAC and fetal bacteremia in all cases (4/4; 100%). Compared to the GBS group, BSCI prophylaxis was associated with significantly lower cytokine levels including lower IL-8 in amniotic fluid (p = 0.03), TNF-α in fetal plasma (p < 0.05), IFN-α and IL-7 in the fetal lung (p = 0.02) and IL-18, 30 April 2020 Coleman et al. Chemokine Inhibition Prevents Preterm Labor IL-2, and IL-7 in the fetal brain (p = 0.03). Neutrophilic chorioamnionitis was common in the BSCI and GBS groups, but was more severe in the BSCI+GBS group with greater myeloperoxidase staining (granulocyte marker) in the amnion and chorion (p < 0.05 vs. GBS). Collectively, these observations indicate that blocking the chemokine response to infection powerfully suppressed uterine contractility, PTL and the cytokine response, but did not prevent MIAC and fetal pneumonia. Development of PTL immunotherapies should occur in tandem with evaluation for AF microbes and consideration for antibiotic therapy.

Group B streptococci (GBS) are Gram-positive β-hemolytic bacteria that can cause serious and life-threatening infections in neonates manifesting as sepsis, pneumonia, meningitis, osteomyelitis, and/or septic arthritis. Invasive GBS infections in neonates in the first week of life are referred to as early-onset disease (EOD) and thought to be acquired by the fetus through exposure to GBS in utero or to vaginal fluids during birth. Late-onset disease (LOD) refers to invasive GBS infections between 7 and 89 days of life. LOD transmission routes are incompletely understood, but may include breast milk, household contacts, nosocomial, or community sources. Invasive GBS infections and particularly meningitis may result in significant neurodevelopmental injury and long-term disability that persists into childhood and adulthood. Globally, EOD and LOD occur in more than 300,000 neonates and infants annually, resulting in 90,000 infant deaths and leaving more than 10,000 infants with a lifelong disability. In this review, we discuss the clinical impact of invasive GBS neonatal infections and then summarize virulence and host factors that allow the bacteria to exploit the developing neonatal immune system and target organs. Specifically, we consider the mechanisms known to enable GBS invasion into the neonatal lung, blood vessels and brain. Understanding mechanisms of GBS invasion and pathogenesis relevant to infections in the neonate and infant may inform the development of therapeutics to prevent or mitigate injury, as well as improve risk stratification.

No abstract