Abstract
Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received choriodecidual inoculation of either GBS (n = 5) or saline (n = 5). Cesarean section was performed in the first week after GBS or saline inoculation. RNA extracted from chorioamnion (inoculation site) was profiled by microarray. Single gene, Gene Set, and Ingenuity Pathway Analysis results were validated using qRT-PCR (chorioamnion), Luminex (amniotic fluid, AF), immunohistochemistry, and transmission electron microscopy (TEM). Despite uterine quiescence in most cases, significant elevations of AF cytokines (TNF-α, IL-8, IL-1β, IL-6) were detected in GBS versus controls (p<0.05). Choriodecidual infection resolved by the time of cesarean section in 3 of 5 cases and GBS was undetectable by culture and PCR in the AF. A total of 331 genes were differentially expressed (>2-fold change, p<0.05). Remarkably, GBS exposure was associated with significantly downregulated expression of multiple cytokeratin (CK) and other cytoskeletal genes critical for maintenance of tissue tensile strength. Immunofluorescence revealed highly significant changes in the CK network within amniocytes with dense CK aggregates and retraction from the cell periphery (all p = 0.006). In human pregnancies affected by PPROM, there was further evidence of CK network retraction with significantly shorter amniocyte foot processes (p = 0.002). These results suggest early choriodecidual infection results in decreased cellular membrane integrity and tensile strength via dysfunction of CK networks. Downregulation of CK expression and perturbations in the amniotic epithelial cell intermediate filament network occur after GBS choriodecidual infection, which may contribute to PPROM.
Highlights
Preterm premature rupture of membranes (PPROM) occurs in 1–2% of all pregnancies, but complicates 30% of all preterm deliveries [1]
We use a nonhuman primate model to show that an early Group B Streptococcus (GBS) infection can damage the structural support of the fetal membranes, the cytokeratin network in the epithelium of the amnion
We obtained human placentas to show that this cytokeratin network was damaged in human patients that had preterm premature rupture of the membranes, a major cause of preterm birth
Summary
Preterm premature rupture of membranes (PPROM) occurs in 1–2% of all pregnancies, but complicates 30% of all preterm deliveries [1]. The majority of women (70%) with PPROM deliver within 24 hours after membrane rupture. The fetal membranes (chorioamnion) are composed of two membranes called the amnion and chorion that enclose the amniotic cavity. Inflammation of the chorioamnion and within the amniotic fluid is thought to play a major role in the pathogenesis of premature rupture resulting in preterm delivery. Infection-associated preterm labor is commonly characterized by elevated amniotic fluid cytokine levels in women and animal models of preterm birth [2,3,4,5,6], In addition to mediating inflammation, cytokines have been associated with
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