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Norovirus Triggered Microbiota-driven Mucosal Inflammation in Interleukin 10-deficient Mice

Basic, Marijana*; Keubler, Lydia M. PhD*; Buettner, Manuela Dr. rer. nat.*; Achard, Marcel Dr. med. vet.*,†; Breves, Gerhard Dr. med. vet.; Schröder, Bernd Dr. rer. nat.; Smoczek, Anna*; Jörns, Anne Dr. med.§; Wedekind, Dirk Dr. rer. nat.*; Zschemisch, Nils H. Dr. rer. nat.*; Günther, Claudia Dr. rer. nat.; Neumann, Detlef Dr. rer. nat.; Lienenklaus, Stefan Dr. rer. nat.**; Weiss, Siegfried Dr. rer. nat.**; Hornef, Mathias W. Dr. med.††; Mähler, Michael Dr. med. vet.; Bleich, André PhD*

Inflammatory Bowel Diseases:
doi: 10.1097/01.MIB.0000441346.86827.ed
Original Basic Science Articles
Abstract

Background: Infection may trigger clinically overt mucosal inflammation in patients with predisposition for inflammatory bowel disease. However, the impact of particular enteropathogenic microorganisms is ill-defined. In this study, the influence of murine norovirus (MNV) infection on clinical, histopathological, and immunological features of mucosal inflammation in the IL10-deficient (Il10−/−) mouse model of inflammatory bowel disease was examined.

Methods: C57BL/6J and C3H/HeJBir wild-type and Il10−/− mice kept under special pathogen-free conditions and devoid of clinical and histopathological signs of mucosal inflammation were monitored after MNV infection for structural and functional intestinal barrier changes by in situ MNV reverse transcription PCR, transgene reporter gene technology, histology, flux measurements, quantitative real-time PCR, immunohistology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. In addition, the influence of the enteric microbiota was analyzed in MNV-infected germfree Il10−/− mice.

Results: Although MNV-infected wild-type mice remained asymptomatic, mucosal inflammation was noted in previously healthy Il10−/− mice 2 to 4 weeks after infection. MNV-induced changes in Il10−/− mice included increased paracellular permeability indicated by increased mucosal mannitol flux, reduced gene expression of tight junction molecules, and an enhanced rate of epithelial apoptosis. MNV-induced reduction of tight junction protein expression and inflammatory lesions were absent in germfree Il10−/− mice, whereas epithelial apoptosis was still observed.

Conclusions: Despite its subclinical course in wild-type animals, MNV causes epithelial barrier disruption in Il10−/− animals representing a potent colitogenic stimulus that largely depends on the presence of the enteric microbiota. MNV might thus trigger overt clinical disease in individuals with a nonsymptomatic predisposition for inflammatory bowel disease by impairment of the intestinal mucosa.

In Brief

Article first published online 30 January 2014

Author Information

*Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany;

BioDoc, Hannover, Germany;

Department of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany;

§Institute for Clinical Biochemistry, Hannover Medical School, Hannover, Germany;

Medical Clinic 1, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany;

Institute of Pharmacology, Hannover Medical School, Hannover, Germany;

**Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; and

††Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

Reprints: André Bleich, PhD, Institute of Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany (e-mail: bleich.andre@mh-hannover.de).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported by a grant from the collaborative research centres SFB621 (Z1), SFB900 (A4), the DFG priority program SPP1656, the DFG-grant BL 953/4-1, and a stipend by the Hannover Biomedical Research School (HBRS), the Centre for Infection Biology (ZIB) to Marijana Basic.

M. Basic and L. M. Keubler contributed equally.

The authors have no conflicts of interest to disclose.

Received October 22, 2013

Accepted December 10, 2013

© Crohn's & Colitis Foundation of America, Inc.

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