Antenatal ureaplasma infection impairs development of the fetal ovine gut in an IL-1-dependent manner

1] Department of Neonatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA [2] Department of Pediatrics, Maastricht University Medical Center (MUMC), School of Oncology and Developmental Biology (GROW), Maastricht, The Netherlands.
Mucosal Immunology (Impact Factor: 7.37). 11/2012; 6(3). DOI: 10.1038/mi.2012.97
Source: PubMed


Ureaplasma infection of the amniotic cavity is associated with adverse postnatal intestinal outcomes. We tested whether interleukin-1 (IL-1) signaling underlies intestinal pathology following ureaplasma exposure in fetal sheep. Pregnant ewes received intra-amniotic injections of ureaplasma or culture media for controls at 3, 7, and 14 d before preterm delivery at 124 d gestation (term 150 d). Intra-amniotic injections of recombinant human interleukin IL-1 receptor antagonist (rhIL-1ra) or saline for controls  were given 3 h before and every 2 d after Ureaplasma injection. Ureaplasma exposure caused fetal gut inflammation within 7 d with damaged villus epithelium and gut barrier loss. Proliferation, differentiation, and maturation of enterocytes were significantly reduced after 7 d of ureaplasma exposure, leading to severe villus atrophy at 14 d. Inflammation, impaired development and villus atrophy of the fetal gut was largely prevented by intra-uterine rhIL-1ra treatment. These data form the basis for a clinical understanding of the role of ureaplasma in postnatal intestinal pathologies.Mucosal Immunology advance online publication 14 November 2012; doi:10.1038/mi.2012.97.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The human fetus is able to mount a systemic inflammatory response when exposed to microorganisms. This stereotypic response has been termed the 'fetal inflammatory response syndrome' (FIRS), defined as an elevation of fetal plasma interleukin-6 (IL-6). FIRS is frequently observed in patients whose preterm deliveries are associated with intra-amniotic infection, acute inflammatory lesions of the placenta, and a high rate of neonatal morbidity. Recently, a novel form of fetal systemic inflammation, characterized by an elevation of fetal plasma CXCL10, has been identified in patients with placental lesions consistent with 'maternal anti-fetal rejection'. These lesions include chronic chorioamnionitis, plasma cell deciduitis, and villitis of unknown etiology. In addition, positivity for human leukocyte antigen (HLA) panel-reactive antibodies (PRA) in maternal sera can also be used to increase the index of suspicion for maternal anti-fetal rejection. The purpose of this study was to determine (i) the frequency of pathologic lesions consistent with maternal anti-fetal rejection in term and spontaneous preterm births; (ii) the fetal serum concentration of CXCL10 in patients with and without evidence of maternal anti-fetal rejection; and (iii) the fetal blood transcriptome and proteome in cases with a fetal inflammatory response associated with maternal anti-fetal rejection. Maternal and fetal sera were obtained from normal term (n = 150) and spontaneous preterm births (n = 150). A fetal inflammatory response associated with maternal anti-fetal rejection was diagnosed when the patients met two or more of the following criteria: (i) presence of chronic placental inflammation; (ii) ≥80% of maternal HLA class I PRA positivity; and (iii) fetal serum CXCL10 concentration >75th percentile. Maternal HLA PRA was analyzed by flow cytometry. The concentrations of fetal CXCL10 and IL-6 were determined by ELISA. Transcriptome analysis was undertaken after the extraction of total RNA from white blood cells with a whole-genome DASL assay. Proteomic analysis of fetal serum was conducted by two-dimensional difference gel electrophoresis. Differential gene expression was considered significant when there was a P < 0.01 and a fold-change >1.5. (i) The frequency of placental lesions consistent with maternal anti-fetal rejection was higher in patients with preterm deliveries than in those with term deliveries (56% versus 32%; P < 0.001); (ii) patients with spontaneous preterm births had a higher rate of maternal HLA PRA class I positivity than those who delivered at term (50% versus 32%; P = 0.002); (iii) fetuses born to mothers with positive maternal HLA PRA results had a higher median serum CXCL10 concentration than those with negative HLA PRA results (P < 0.001); (iv) the median serum CXCL10 concentration (but not IL-6) was higher in fetuses with placental lesions associated with maternal anti-fetal rejection than those without such lesions (P < 0.001); (v) a whole-genome DASL assay of fetal blood RNA demonstrated differential expression of 128 genes between fetuses with and without lesions associated with maternal anti-fetal rejection; and (vi) comparison of the fetal serum proteome demonstrated 20 proteins whose abundance differed between fetuses with and without lesions associated with maternal anti-fetal rejection. We describe a systemic inflammatory response in human fetuses born to mothers with evidence of maternal anti-fetal rejection. The transcriptome and proteome of this novel type of fetal inflammatory response were different from that of FIRS type I (which is associated with acute infection/inflammation).
    No preview · Article · Jul 2013 · American Journal Of Reproductive Immunology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The genital mycoplasma species, Ureaplasma parvum and Ureaplasma urealyticum are the most common organisms isolated from infected amniotic fluid and placentas, and they contribute to adverse pregnancy outcomes including preterm birth and neonatal morbidities. In our institution, almost half of the preterm infants of less than 32 weeks gestation are Ureaplasma-positive in one or more compartment (respiratory, blood and/or cerebrospinal fluid), indicating that these organisms are the most common pathogens affecting this population. This review will focus on the compelling epidemiological and experimental evidence linking perinatal Ureaplasma species exposure to important morbidities of prematurity, such as bronchopulmonary dysplasia, intraventricular haemorrhage and necrotising enterocolitis.
    Preview · Article · Aug 2013 · Archives of Disease in Childhood - Fetal and Neonatal Edition
  • [Show abstract] [Hide abstract]
    ABSTRACT: With the advent of the Human Microbiome Project, wherein new high throughput technologies are employed to evaluate the taxonomy and function of microbes residing in various regions of the body, there is increasing recognition of the scope and clinical significance of the intestinal microbiota. The total number of bacterial cells residing in human intestine far exceeds the number of host cells. More than 3 million genes have been identified in this microbiota, which is more than 100-fold of our own human genes. Although commonly thought to be related to disease as pathogens, the majority of microbes of the intestine are commensals and symbionts that benefit the host in terms of nutrition, development of the immune system, and postnatalmaturation of the intestine. They perform helpful functions that cannot be performed by the human host itself. This review aims to summarize recently emerging knowledge on the intestine microbiome in the antenatal, perinatal, and postnatal periods. We will limit our discussion to the fetal microbiome, the effects of cesarean delivery versus vaginal delivery, and the relationship of the microbiome to necrotizing enterocolitis, late-onset sepsis, and the developing brain. © 2013 by the American Academy of Pediatrics. All rights reserved.
    No preview · Article · Dec 2013 · NeoReviews
Show more