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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure

Authors: Daan R. M. G. Ophelders, Ruth Gussenhoven, Martin Lammens, Benno Küsters, Matthew W. Kemp, John P. Newnham, Matthew S. Payne, Suhas G. Kallapur, Allan H. Jobe, Luc J. Zimmermann, Boris W. Kramer, Tim G. A. M. Wolfs

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Intra-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.

Methods

Pregnant 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.

Results

Intra-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.

Conclusions

Intra-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.
Appendix
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Metadata
Title
Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure
Authors
Daan R. M. G. Ophelders
Ruth Gussenhoven
Martin Lammens
Benno Küsters
Matthew W. Kemp
John P. Newnham
Matthew S. Payne
Suhas G. Kallapur
Allan H. Jobe
Luc J. Zimmermann
Boris W. Kramer
Tim G. A. M. Wolfs
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0492-z

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