title: Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease.
abstract: Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTregconversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Romain
authors.identifier: 0000-0001-7649-7306
authors.initials: R
authors.lastname: Bouziat
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Reinhard
authors.identifier: 0000-0002-6518-108X
authors.initials: R
authors.lastname: Hinterleitner
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Judy J
authors.identifier: 0000-0003-2608-3169
authors.initials: JJ
authors.lastname: Brown
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Stencel-Baerenwald
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Mine
authors.initials: M
authors.lastname: Ikizler
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Toufic
authors.identifier: 0000-0002-5458-1352
authors.initials: T
authors.lastname: Mayassi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Sangman M
authors.identifier: 0000-0002-8204-0393
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Department of Translational Medical Sciences, Section of Pediatrics, University of Naples Federico II, and CeInGe-Biotecnologie Avanzate, Naples, Italy.
authors.forename: Valentina
authors.identifier: 0000-0001-6158-0545
authors.initials: V
authors.lastname: Discepolo
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Pruijssers
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Jordan D
authors.identifier: 0000-0003-0857-217X
authors.initials: JD
authors.lastname: Ernest
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Iskarpatyoti
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands.
authors.forename: Léa M M
authors.initials: LM
authors.lastname: Costes
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Ian
authors.identifier: 0000-0003-4032-5611
authors.initials: I
authors.lastname: Lawrence
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA, USA.
authors.forename: Brad A
authors.identifier: 0000-0002-4049-4274
authors.initials: BA
authors.lastname: Palanski
authors.affiliation: Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
authors.forename: Mukund
authors.identifier: 0000-0002-9254-1247
authors.initials: M
authors.lastname: Varma
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|Committee on Immunology, University of Chicago, Chicago, IL, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Zurenski
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Solomiia
authors.initials: S
authors.lastname: Khomandiak
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Nicole
authors.identifier: 0000-0002-2641-4813
authors.initials: N
authors.lastname: McAllister
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Aravamudhan
authors.affiliation: Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Karl W
authors.identifier: 0000-0003-2691-9763
authors.initials: KW
authors.lastname: Boehme
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Fengling
authors.initials: F
authors.lastname: Hu
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center Rotterdam-Sophia Children's Hospital, Rotterdam, Netherlands.
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
authors.affiliation: Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Hans-Christian
authors.identifier: 0000-0001-8283-644X
authors.initials: HC
authors.lastname: Reinecker
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Kupfer
authors.affiliation: University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.|Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guandalini
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.|University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Semrad
authors.affiliation: Department of Microbiology, Infectiology, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Abadie
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA, USA.|Department of Chemical Engineering, Stanford University, Stanford, CA, USA.|Stanford ChEM-H, Stanford University, Stanford, California, USA.
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.affiliation: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Luis B
authors.identifier: 0000-0001-9456-367X
authors.initials: LB
authors.lastname: Barreiro
authors.affiliation: Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard University, Cambridge, MA, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Ramnik J
authors.identifier: 0000-0002-5630-5167
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Division of Gastroenterology, Department of Medicine, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. bjabri@bsd.uchicago.edu terence.dermody@chp.edu.|Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Terence S
authors.identifier: 0000-0003-1853-8741
authors.initials: TS
authors.lastname: Dermody
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA. bjabri@bsd.uchicago.edu terence.dermody@chp.edu.|Committee on Immunology, University of Chicago, Chicago, IL, USA.|University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.|Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.|Department of Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: Bana
authors.identifier: 0000-0001-7427-4424
authors.initials: B
authors.lastname: Jabri
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D002446:Celiac Disease / Q000276:immunology* / Q000821:virology*; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005818:Genetic Engineering; D005983:Glutens / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology / Q000821:virology*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D012087:Reoviridae / Q000235:genetics; D012088:Reoviridae Infections / Q000150:complications* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000941:Antigens; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D005983:Glutens