title: Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.
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 10(7) 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.
authors: Department of Pediatrics, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. d.ophelders@maastrichtuniversity.nl.|School of Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands. d.ophelders@maastrichtuniversity.nl.
authors: Daan R M G
authors: DR
authors: Ophelders
authors: Department of Pediatrics, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. r.gussenhoven@maastrichtuniversity.nl.|School of Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands. r.gussenhoven@maastrichtuniversity.nl.
authors: Ruth
authors: R
authors: Gussenhoven
authors: Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. martin.lammens@uza.be.
authors: Martin
authors: M
authors: Lammens
authors: Department of Pathology, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. b.kuesters@radboudumc.nl.
authors: Benno
authors: B
authors: Küsters
authors: School of Women's and Infants' Health, The University of Western Australia (M550), 35 Stirling Highway, Crawley, WA, 6009, Australia. matthew.kemp@uwa.edu.au.
authors: Matthew W
authors: MW
authors: Kemp
authors: School of Women's and Infants' Health, The University of Western Australia (M550), 35 Stirling Highway, Crawley, WA, 6009, Australia. john.newnham@uwa.edu.au.
authors: John P
authors: JP
authors: Newnham
authors: School of Women's and Infants' Health, The University of Western Australia (M550), 35 Stirling Highway, Crawley, WA, 6009, Australia. matthew.payne@uwa.edu.au.
authors: Matthew S
authors: MS
authors: Payne
authors: Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45208, USA. suhas.Kallapur@cchmc.org.
authors: Suhas G
authors: SG
authors: Kallapur
authors: Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45208, USA. alan.jobe@cchmc.org.
authors: Allan H
authors: AH
authors: Jobe
authors: Department of Pediatrics, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. luc.zimmermann@mumc.nl.|School of Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, Maastricht, 6229 ER, The Netherlands. luc.zimmermann@mumc.nl.
authors: Luc J
authors: LJ
authors: Zimmermann
authors: Department of Pediatrics, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. b.kramer@maastrichtuniversity.nl.|School of Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, Maastricht, 6229 ER, The Netherlands. b.kramer@maastrichtuniversity.nl.|School of Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, Maastricht, 6229 ER, The Netherlands. b.kramer@maastrichtuniversity.nl.
authors: Boris W
authors: BW
authors: Kramer
authors: Department of Pediatrics, Maastricht University Medical Center, PO box 5800, Maastricht, 6202 AZ, The Netherlands. tim.wolfs@maastrichtuniversity.nl.|School of Oncology and Developmental Biology, Maastricht University, Universiteitssingel 50, Maastricht, 6229 ER, The Netherlands. tim.wolfs@maastrichtuniversity.nl.
authors: Tim G A M
authors: TG
authors: Wolfs
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D002135:Calcium-Binding Proteins; D002176:Candida albicans / Q000472:pathogenicity*; D002177:Candidiasis / Q000150:complications*; D053148:Caspase 3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology* / Q000382:microbiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012756:Sheep
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005452:Fluoresceins; D007377:Interleukin-3; D015850:Interleukin-6; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C534582:fluoro-jade C; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; D053148:Caspase 3