title: Choriodecidual Group B Streptococcal Infection Induces miR-155-5p in the Fetal Lung in Macaca nemestrina.
abstract: The mechanisms underlying fetal lung injury remain poorly defined. MicroRNAs (miRNAs) are small noncoding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. Using a nonhuman primate model of choriodecidual infection, we sought to determine if differentially expressed miRNAs were associated with acute fetal lung injury. After inoculating 10 chronically catheterized pregnant monkeys (Macaca nemestrina) with either group B streptococcus (GBS) at 1 × 10(6) CFU (n = 5) or saline (n = 5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled the changes in expression by microarray analysis. We identified 9 differentially expressed miRNAs in GBS-exposed fetal lungs, but of these, only miR-155-5p was validated by quantitative reverse transcription-PCR (P = 0.02). Significantly elevated miR-155-5p expression was also observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]). Overexpression of miR-155-5p in FeAE cells in turn increased the production of IL-6 and CXCL10/gamma interferon-induced protein 10, which are implicated in leukocyte recruitment but also in protection from lung injury. Interestingly, while miR-155-5p decreased fibroblast growth factor 9 (FGF9) expression in a luciferase reporter assay, FGF9 levels were actually increased in GBS-exposed fetal lungs in vivo. FGF9 overexpression is associated with abnormal lung development. Thus, upregulation of miR-155-5p may serve as a compensatory mechanism to lessen the increase in FGF9 and prevent aberrant lung development. Understanding the complicated networks regulating lung development in the setting of infection is a key step in identifying how to prevent fetal lung injury leading to bronchopulmonary dysplasia.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: McAdams
authors.affiliation: Department of Pediatric Infectious Diseases, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Bierle
authors.affiliation: Department of Pediatric Infectious Diseases, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Boldenow
authors.affiliation: Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Weed
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Tsai
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: MacDonald
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.affiliation: Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Vanderhoeven
authors.affiliation: Department of Pediatric Infectious Diseases, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, Washington, USA lakshmi.rajagopal@seattlechildrens.org adamsk@u.washington.edu.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA lakshmi.rajagopal@seattlechildrens.org adamsk@u.washington.edu.
authors.forename: Kristina M
authors.identifier: http://orcid.org/0000-0002-6939-7224
authors.initials: KM
authors.lastname: Adams Waldorf
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005315:Fetal Diseases / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000254:growth & development / Q000378:metabolism* / Q000382:microbiology; D008254:Macaca nemestrina; D008297:Male; D011247:Pregnancy; D013290:Streptococcal Infections / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D013291:Streptococcus / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha