TY - JOUR
T1 - Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease
AU - Bouziat, Romain
AU - Hinterleitner, Reinhard
AU - Brown, Judy J.
AU - Stencel-Baerenwald, Jennifer E.
AU - Ikizler, Mine
AU - Mayassi, Toufic
AU - Meisel, Marlies
AU - Kim, Sangman M.
AU - Discepolo, Valentina
AU - Pruijssers, Andrea J.
AU - Ernest, Jordan D.
AU - Iskarpatyoti, Jason A.
AU - Costes, Léa M.M.
AU - Lawrence, Ian
AU - Palanski, Brad A.
AU - Varma, Mukund
AU - Zurenski, Matthew A.
AU - Khomandiak, Solomiia
AU - McAllister, Nicole
AU - Aravamudhan, Pavithra
AU - Boehme, Karl W.
AU - Hu, Fengling
AU - Samsom, Janneke N.
AU - Reinecker, Hans Christian
AU - Kupfer, Sonia S.
AU - Guandalini, Stefano
AU - Semrad, Carol E.
AU - Abadie, Valérie
AU - Khosla, Chaitan
AU - Barreiro, Luis B.
AU - Xavier, Ramnik J.
AU - Ng, Aylwin
AU - Dermody, Terence S.
AU - Jabri, Bana
N1 - Funding Information:
Library generation and sequencing was performed by the University of Chicago Genomics Facility (http://genomics.bsd. jchicago.edu). Data reported in this paper were deposited into the National Center for Biotechnology Information Gene Expressior Omnibus database under the SuperSeries record GSE94604 containing the following SubSeries records: GSE94602 (RNA-sec data) and GSE94517 (Microarray data). Histological slides were generated by the Vanderbilt Translational Pathology Shared Resource supported by National Cancer Institute/National Institutes of Health Cancer Center Support Grant P30 CA068485 and the Vanderbilt Mouse Metabolic Phenotyping Center Grant U24 DK059637. Whole-slide imaging and quantification of immunostaining were performed in the Digital Histology Shared Resource at Vanderbilt University Medical Center (www.mc. vanderbilt.edu/dhsr). We thank P. Savage (University of Chicago) for providing OT-II mice. We thank D. Mucida and D. Esterhazy (The Rockefeller University) for expertise and reagents. We thank B. Xiang for technical assistance. We thank T. Golovkina for helpful suggestions and discussions. This work was supported by the following grants from the NIH: R01DK098435 to B.J., T.S.D., and R.J.X; R01DK100619 and R01DK067180 to B.J.; R01AI038296 to T.S.D.; R01DK43351 to R.J.X.; F31DK108562 to J.J.B.; R01DK063158 to C.K.; and R01AI113333 and R01DK068181 to H.-C.R. Additional support includes a Cancer Center Support Grant P30CA014599 and Digestive Diseases Research Core Center P30 DK42086 at the University of Chicago to B.J.; an Investigator Start-up Fund, Department of Medicine, MGH to A.N.; an award from the Bettencourt Schueller Foundation to R.B.; a research fellowship from the Dutch Sophia Research Foundation to L.M.M.C.; and the Austrian Science Fund (FWF) J3408-B13 to R.H Analysis of patient samples in this work was approved by the nstitutional Review Board of the University of Chicago (protocol 12623B) and Vanderbilt University (protocol 151358). Last, we thank the CeD patients and their family members as well as the University of Chicago Celiac Disease Center for supporting our research.
PY - 2017/4/7
Y1 - 2017/4/7
N2 - 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 pTreg conversion, 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.
AB - 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 pTreg conversion, 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.
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U2 - 10.1126/science.aah5298
DO - 10.1126/science.aah5298
M3 - Article
C2 - 28386004
AN - SCOPUS:85017383204
VL - 356
SP - 44
EP - 50
JO - Science
JF - Science
SN - 0036-8075
IS - 6333
ER -