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Abstract
Streptococcus agalactiae, or group B Streptococcus (GBS), is a common perinatal pathogen. GBS colonization of the vaginal mucosa during pregnancy is a risk factor for invasive infection of the fetal membranes (chorioamnionitis) and its consequences such as membrane rupture, preterm labor, stillbirth, and neonatal sepsis. Placental macrophages, or Hofbauer cells, are fetally derived macrophages present within placental and fetal membrane tissues that perform vital functions for fetal and placental development, including supporting angiogenesis, tissue remodeling, and regulation of maternal-fetal tolerance. Although placental macrophages as tissue-resident innate phagocytes are likely to engage invasive bacteria such as GBS, there is limited information regarding how these cells respond to bacterial infection. Here, we demonstrate in vitro that placental macrophages release macrophage extracellular traps (METs) in response to bacterial infection. Placental macrophage METs contain proteins, including histones, myeloperoxidase, and neutrophil elastase similar to neutrophil extracellular traps, and are capable of killing GBS cells. MET release from these cells occurs by a process that depends on the production of reactive oxygen species. Placental macrophage METs also contain matrix metalloproteases that are released in response to GBS and could contribute to fetal membrane weakening during infection. MET structures were identified within human fetal membrane tissues infected ex vivo, suggesting that placental macrophages release METs in response to bacterial infection during chorioamnionitis.IMPORTANCE Streptococcus agalactiae, also known as group B Streptococcus (GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis. Mechanisms by which GBS infection results in adverse pregnancy outcomes are still incompletely understood. This study evaluated interactions between GBS and placental macrophages. The data demonstrate that in response to infection, placental macrophages release extracellular traps capable of killing GBS. Additionally, this work establishes that proteins associated with extracellular trap fibers include several matrix metalloproteinases that have been associated with chorioamnionitis. In the context of pregnancy, placental macrophage responses to bacterial infection might have beneficial and adverse consequences, including protective effects against bacterial invasion, but they may also release important mediators of membrane breakdown that could contribute to membrane rupture or preterm labor.
Highlights
IMPORTANCE Streptococcus agalactiae, known as group B Streptococcus (GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis
To determine whether these structures were macrophage extracellular traps (METs), macrophages were evaluated by scanning laser confocal microscopy after staining with the DNA binding dye SYTOX Green, which demonstrated extracellular structures extending from placental macrophages (PMs) that were not seen when PMs were treated with DNase I (Fig. 1A, top panels)
MET release by PMs occurred in a dose-dependent fashion (Fig. S2A), and MET release was not GBS strain or bacterial species specific, as PMs infected with GBS strain GB037, a capsular type V strain, Escherichia coli, or heat-killed bacteria resulted in similar MET release (Fig. S3)
Summary
IMPORTANCE Streptococcus agalactiae, known as group B Streptococcus (GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis. In the context of pregnancy, placental macrophage responses to bacterial infection might have beneficial and adverse consequences, including protective effects against bacterial invasion, but they may release important mediators of membrane breakdown that could contribute to membrane rupture or preterm labor. Bacterial products are recognized by pathogen recognition receptors, which stimulate production of proinflammatory cytokines [20, 22, 23] These inflammatory mediators initiate a cascade of events that result in neutrophil infiltration into the fetal membranes, production and release of matrix metalloproteases (MMPs), and cervical contractions which eventually result in membrane rupture and preterm birth [24]. PM METs contain histones, myeloperoxidase, and neutrophil elastase as well as
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