Abstract
Streptococcus agalactiae, or Group B Streptococcus (GBS), is a gram-positive bacterial pathogen associated with infection during pregnancy and is a major cause of morbidity and mortality in neonates. Infection of the extraplacental membranes surrounding the developing fetus, a condition known as chorioamnionitis, is characterized histopathologically by profound infiltration of polymorphonuclear cells (PMNs, neutrophils) and greatly increases the risk for preterm labor, stillbirth, or neonatal GBS infection. The advent of animal models of chorioamnionitis provides a powerful tool to study host-pathogen relationships in vivo and ex vivo. The purpose of this study was to evaluate the innate immune response elicited by GBS and evaluate how antimicrobial strategies elaborated by these innate immune cells affect bacteria. Our work using a mouse model of GBS ascending vaginal infection during pregnancy reveals that clinically isolated GBS has the capacity to invade reproductive tissues and elicit host immune responses including infiltration of PMNs within the choriodecidua and placenta during infection, mirroring the human condition. Upon interacting with GBS, murine neutrophils elaborate DNA-containing extracellular traps, which immobilize GBS and are studded with antimicrobial molecules including lactoferrin. Exposure of GBS to holo- or apo-forms of lactoferrin reveals that the iron-sequestration activity of lactoferrin represses GBS growth and viability in a dose-dependent manner. Together, these data indicate that the mouse model of ascending infection is a useful tool to recapitulate human models of GBS infection during pregnancy. Furthermore, this work reveals that neutrophil extracellular traps ensnare GBS and repress bacterial growth via deposition of antimicrobial molecules, which drive nutritional immunity via metal sequestration strategies.
Highlights
We demonstrate that Group B Streptococcus (GBS)-neutrophil interaction results in the elaboration of neutrophil extracellular traps (NETs) decorated with the antimicrobial protein lactoferrin
Our results reveal that GBS colonizes surface of the vagina (Supplemental Figure 1, Figure 2) at an average burden of 3.6 × 106 colony forming units (CFU)/mg of tissue, and the bacterial colonization is spatially oriented at the lumen of the tissue within the vaginal mucosa as determined by IHC microscopic examination (Supplemental Figure 1)
IHC microscopic analyses reveal GBS ascends in this model and colonizes at the lumen of the endometrium within the uterus, averaging 2.2 × 109 CFU/mg (Supplemental Figure 2)
Summary
Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading cause of adverse pregnancy and neonatal outcomes including stillbirth, chorioamnionitis, preterm birth, and neonatal sepsis and meningitis (Verani et al, 2010; Koumans et al, 2012; Kwatra et al, 2014; Kim et al, 2015). The CDC recommends routine GBS screening during late pregnancy and antibiotic prophylaxis for those testing positive (Koumans et al, 2012). Despite this intervention, GBS remains the leading infectious cause of morbidity and mortality among neonates in the United States (Verani et al, 2010) GBS remains the leading infectious cause of morbidity and mortality among neonates in the United States (Verani et al, 2010).
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