Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells

Barbara Ruder (First author), Vinay Murtadak, Michael Stürzl, Stefan Wirtz, Ute Distler, Stefan Tenzer, Mousumi Mahapatro, Florian R Greten, Yinling Hu, Markus F Neurath, Ethel Cesarman, Gianna Ballon, Claudia Günther, Christoph Becker

Research output: Contribution to journalOriginal Articlepeer-review

Abstract

Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlipIEC-tg mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vFlip expression altered classical and alternative NFκB activation. Blocking of alternative NFκB signaling by deletion of Ikka in vivo largely protected mice from inflammation and Paneth cell loss induced by vFLIP. Collectively, our data provide functional evidence that expression of a single viral protein in IECs can be sufficient to disrupt epithelial homeostasis and to initiate chronic intestinal inflammation.

Original languageEnglish
Pages (from-to)1621-1629
Number of pages9
JournalMucosal immunology
Volume11
Issue number6
DOIs
Publication statusPublished - Nov 2018
Externally publishedYes

Keywords

  • Animals
  • Cells, Cultured
  • Enterocytes/pathology
  • Gene Expression Regulation
  • Herpesviridae Infections/metabolism
  • Herpesvirus 8, Human/genetics
  • Homeostasis
  • Humans
  • I-kappa B Kinase/genetics
  • Inflammatory Bowel Diseases/pathology
  • Intestines/pathology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B/genetics
  • Necrosis
  • Viral Proteins/metabolism

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