Abstract
BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 107 colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0492-z) contains supplementary material, which is available to authorized users.
Highlights
IntroductionThe microorganisms most frequently associated with this condition include Ureaplasma species, Mycoplasma hominis, and Gardnerella vaginalis, all of which most commonly originate from the lower reproductive tract [3]
Preterm birth is associated with chorioamnionitis which is defined as inflammation of the fetal membranes and amniotic fluid caused by microbial invasion [1, 2]
Positive cerebrospinal fluid (CSF) cultures for C. albicans were detected in 67 % (4/6) of the 3-day C. albicans-exposed animals and in 50 % (3/6) of the 3-day C. albicans-/fluconazole-treated animals (Table 1)
Summary
The microorganisms most frequently associated with this condition include Ureaplasma species, Mycoplasma hominis, and Gardnerella vaginalis, all of which most commonly originate from the lower reproductive tract [3] These microorganisms and/or inflammatory mediators in the amniotic cavity can cause a fetal inflammatory response syndrome (FIRS) [4,5,6]. Adverse neurodevelopmental outcomes result from diffuse cerebral inflammation and white matter injury, periventricular leukomalacia, and intraventricular hemorrhage [5, 8, 9] These conditions are associated with a high mortality rate, and survivors are predisposed to longterm morbidity including mental retardation, impaired learning, visual disorders, and in severe cases, cerebral palsy [7, 8, 10]
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