title: Intra-amniotic Candida albicans infection induces mucosal injury and inflammation in the ovine fetal intestine.
abstract: Chorioamnionitis is caused by intrauterine infection with microorganisms including Candida albicans (C.albicans). Chorioamnionitis is associated with postnatal intestinal pathologies including necrotizing enterocolitis. The underlying mechanisms by which intra-amniotic C.albicans infection adversely affects the fetal gut remain unknown. Therefore, we assessed whether intra-amniotic C.albicans infection would cause intestinal inflammation and mucosal injury in an ovine model. Additionally, we tested whether treatment with the fungistatic fluconazole ameliorated the adverse intestinal outcome of intra-amniotic C.albicans infection. Pregnant sheep received intra-amniotic injections with 10(7) colony-forming units C.albicans or saline at 3 or 5 days before preterm delivery at 122 days of gestation. Fetuses were given intra-amniotic and intra-peritoneal fluconazole treatments 2 days after intra-amniotic administration of C.albicans. Intra-amniotic C.albicans caused intestinal colonization and invasive growth within the fetal gut with mucosal injury and intestinal inflammation, characterized by increased CD3(+) lymphocytes, MPO(+) cells and elevated TNF-α and IL-17 mRNA levels. Fluconazole treatment in utero decreased intestinal C.albicans colonization, mucosal injury but failed to attenuate intestinal inflammation. Intra-amniotic C.albicans caused intestinal infection, injury and inflammation. Fluconazole treatment decreased mucosal injury but failed to ameliorate C.albicans-mediated mucosal inflammation emphasizing the need to optimize the applied antifungal therapeutic strategy.
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Esmee M R
authors.initials: EM
authors.lastname: Jacobs
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.affiliation: Institute of Medical Microbiology, RWTH University Hospital, Aachen, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Payne
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.|Division of Perinatal Medicine, Tohoku University Hospital, Sendai, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Saito
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Leon E W
authors.initials: LE
authors.lastname: Janssen
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Jobe
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands.|School of Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands.|School of Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.|Department of Biomedical Engineering, Maastricht University, Maastricht, the Netherlands.
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000502:physiology*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology / Q000662:veterinary*; D002821:Chorioamnionitis / Q000188:drug therapy / Q000382:microbiology / Q000662:veterinary*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015725:Fluconazole / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D007249:Inflammation / Q000382:microbiology / Q000662:veterinary*; D007413:Intestinal Mucosa / Q000196:embryology / Q000382:microbiology* / Q000473:pathology; D011247:Pregnancy; D012756:Sheep; D012757:Sheep Diseases / Q000382:microbiology* / Q000473:pathology
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D015725:Fluconazole