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Membrane Inflammasome activation by Choriodecidual Ureaplasma parvum infection without intra-amniotic infection in an NHP model.
Biology of Reproduction 2024 Februrary 10
Intrauterine infection is a significant cause of preterm labor and neonatal morbidity and mortality. Ureaplasma parvum is the microorganism most commonly isolated from cases of preterm birth and preterm premature rupture of membranes (pPROM). However, the mechanisms during the early stages of ascending reproductive tract infection remain poorly understood. To examine inflammation in fetal (chorioamnionic) membranes in response to U. parvum infection, we utilized a non-human primate (NHP) model of choriodecidual infection. Eight chronically catheterized pregnant rhesus macaques underwent maternal-fetal catheterization surgery at ~105-112d gestation and choriodecidual inoculation with U. parvum (105cfu/mL, n = 4) or sterile media (Controls; n = 4) starting at 115-119d, repeated at 5d intervals until C-section at 136-140d (term = 167d). The average inoculation to delivery interval was 21d and Ureaplasma infection of the amniotic fluid (AF) was undetectable in all animals. Choriodecidual Ureaplasma infection resulted in increased fetal membrane protein and gene expression of MMP-9 and PTGS2, but did not result in preterm labor or increased concentrations of AF pro-inflammatory cytokines. However, membrane expression of inflammasome sensor molecules, NLRP3, NLRC4, AIM2 and NOD2, and adaptor protein ASC (PYCARD) gene expression were significantly increased. Gene expression of IL-1β, IL-18, the IL-18R1 receptor, CASPASE-1 and pro-CASPASE-1 protein were increased with Ureaplasma infection. Downstream inflammatory genes MYD88 and NFKB were also significantly upregulated. These results demonstrate that at early stages of ascending reproductive tract Ureaplasma infection, activation of inflammasome complexes and pathways associated with degradation of membrane integrity, pPROM and preterm labor are initiated prior to microbes being detectable in the amniotic fluid.
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