The Paradoxical Effects of Chronic Intra-Amniotic Ureaplasma parvum Exposure on Ovine Fetal Brain Development

Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize that re-exposure to an inflammatory trigger during the perinatal period might be responsible for the variation in brain outcome of preterms following Ureaplasma driven chorioamnionitis. To investigate these clinical scenarios, we performed a detailed multi-modal study in which ovine neurodevelopmental outcomes were assessed following chronic intra-amniotic Ureaplasma parvum (UP) infection, either alone or combined with subsequent lipopolysaccharide (LPS) exposure. We show that chronic intra-amniotic UP exposure during the second trimester provoked a decrease of astrocytes, increased oligodendrocyte numbers and elevated 5-methylcytosine levels. In contrast, short-term LPS exposure before preterm birth induced increased microglial activation, myelin loss, elevation of 5-hydroxymethylcytosine levels and lipid profile changes. These LPS-induced changes were prevented by chronic pre-exposure to UP (preconditioning). These data indicate that chronic UP exposure provokes dual effects on preterm brain development in utero. On one hand, prolonged UP exposure causes detrimental cerebral changes which may predispose to adverse postnatal clinical outcomes. On the other, chronic intra-amniotic UP exposure preconditions the brain against a second inflammatory hit. This study demonstrates that microbial interactions, timing and duration of inflammatory insults will determine the effects on the fetal brain. Therefore, this study helps to understand the complex and diverse postnatal neurological outcomes following UP driven chorioamnionitis