title: Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes.
abstract: BACKGROUND
  Children with risk alleles at the 17q21 genetic locus who wheeze during rhinovirus illnesses have a greatly increased likelihood of developing childhood asthma. In mice, overexpression of the 17q21 gene ORMDL3 leads to airway remodelling and hyperresponsiveness. However, the mechanisms by which ORMDL3 predisposes to asthma are unclear. Previous studies have suggested that ORMDL3 induces endoplasmic reticulum (ER) stress and production of the type I interferon (IFN)-regulated chemokine CXCL10.
  
  
  OBJECTIVE
  The purpose of this study was to determine the relationship between ORMDL3 and rhinovirus-induced ER stress and type I IFN in human leucocytes.
  
  
  METHODS
  ER stress was monitored by measuring HSPA5, CHOP and spliced XBP1 gene expression, and type I IFN by measuring IFNB1 (IFN-β) and CXCL10 expression in human cell lines and primary leucocytes following treatment with rhinovirus. Requirements for cell contact and specific cell type in ORMDL3 induction were examined by transwell assay and depletion experiments, respectively. Finally, the effects of 17q21 genotype on the expression of ORMDL3, IFNB1 and ER stress genes were assessed.
  
  
  RESULTS
  THP-1 monocytes overexpressing ORMDL3 responded to rhinovirus with increased IFNB1 and HSPA5. Rhinovirus-induced ORMDL3 expression in primary leucocytes required cell-cell contact, and induction was suppressed by plasmacytoid dendritic cell depletion. The degree of rhinovirus-induced ORMDL3, HSPA5 and IFNB1 expression varied by leucocyte type and 17q21 genotype, with the highest expression of these genes in the asthma-associated genotype.
  
  
  CONCLUSIONS
  Multiple lines of evidence support an association between higher ORMDL3 and increased rhinovirus-induced HSPA5 and type I IFN gene expression. These associations with ORMDL3 are cell type specific, with the most significant 17q21 genotype effects on ORMDL3 expression and HSPA5 induction evident in B cells. Together, these findings have implications for how the interaction of increased ORMDL3 and rhinovirus may predispose to asthma.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: V
authors.initials: V
authors.lastname: Rajamanikham
authors.affiliation: Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Baron
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Mathur
authors.affiliation: Division of Allergy, Pulmonary and Critical Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Schwantes
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ober
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Jackson
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Gern
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J A
authors.identifier: http://orcid.org/0000-0003-4158-8253
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000328:Adult; D001249:Asthma / Q000209:etiology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010850:Picornaviridae Infections / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D012229:Rhinovirus / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007370:Interferon Type I; D008565:Membrane Proteins; C464399:ORMDL3 protein, human
keywords: 17q21; IFN=beta unfolded protein response; ORMDL3; Rhinovirus; asthma; basic mechanisms