Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection

Pedro P Hernández; Tanel Mahlakoiv; Ines Yang; Vera Schwierzeck; Nam Nguyen; Fabian Guendel; Konrad Gronke; Bernhard Ryffel; Christoph Hoelscher; Laure Dumoutier; Jean-Christophe Renauld; Sebastian Suerbaum; Peter Staeheli; Andreas Diefenbach

doi:10.1038/ni.3180

Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection

Nat Immunol. 2015 Jul;16(7):698-707. doi: 10.1038/ni.3180. Epub 2015 May 25.

Authors

Pedro P Hernández^#^{1

2

3}, Tanel Mahlakoiv^#^{4

5}, Ines Yang⁶, Vera Schwierzeck^{1

2}, Nam Nguyen², Fabian Guendel^{1

2

7}, Konrad Gronke^{1

2

3}, Bernhard Ryffel⁸, Christoph Hoelscher^{9

10}, Laure Dumoutier¹¹, Jean-Christophe Renauld¹¹, Sebastian Suerbaum⁶, Peter Staeheli⁴, Andreas Diefenbach^{1

2

7}

Affiliations

¹ Research Centre Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.
² Department of Medical Microbiology and Hygiene, Institute for Medical Microbiology and Hygiene, Freiburg University Medical Centre, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
³ Max-Planck-Institute for Immunobiology and Epigenetics, Stübeweg 51, D-79108 Freiburg, Germany.
⁴ Department of Medical Microbiology and Hygiene, Institute for Virology, Freiburg University Medical Centre, Hermann-Herder-Strasse 11, D-79104 Freiburg, Germany.
⁵ Spemann Graduate School of Biology and Medicine, University of Freiburg, Albertstrasse 19A, D-79104 Freiburg, Germany.
⁶ Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany and DZIF - German Center for Infection Research, Hannover-Braunschweig Site, D-30625 Hannover, Germany.
⁷ Research Training Group (GRK1104) of Organogenesis, Hauptstrasse 1, D-79104 Freiburg, Germany.
⁸ INEM - UMR7355, Molecular Immunology, University and CNRS, F-45071 Orleans, France and Institute of Infectious Disease, University of Cape Town, RSA.
⁹ Infection Immunology Research, Research Center Borstel, D-23845 Borstel, Germany.
¹⁰ Cluster of Excellence Inflammation at Interfaces (Borstel-Kiel-Lübeck-Plön).
¹¹ Ludwig Institute for Cancer Research, Université Catholique de Louvain, 74 Avenue Hippocrate, B-1200 Brussels, Belgium.

^# Contributed equally.

PMID: 26006013
PMCID: PMC4589158
DOI: 10.1038/ni.3180

Abstract

The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caco-2 Cells
Cell Line
Chlorocebus aethiops
Cytokines / genetics
Cytokines / immunology*
Cytokines / pharmacology
Dogs
Drug Synergism
Epithelial Cells / immunology
Epithelial Cells / metabolism
Epithelial Cells / virology
Gene Expression / drug effects
Gene Expression / immunology*
HT29 Cells
Humans
Immunoblotting
Interleukin-22
Interleukins / genetics
Interleukins / immunology*
Interleukins / pharmacology
Intestinal Mucosa / metabolism
Intestines / immunology
Intestines / virology
Madin Darby Canine Kidney Cells
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Molecular Sequence Data
Receptors, Cytokine / genetics
Receptors, Cytokine / immunology
Reverse Transcriptase Polymerase Chain Reaction
Rotavirus Infections / genetics
Rotavirus Infections / immunology*
Rotavirus Infections / virology
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / immunology
STAT1 Transcription Factor / metabolism
Vero Cells

Substances

Cytokines
Interleukins
Receptors, Cytokine
STAT1 Transcription Factor
interferon-lambda protein, mouse

Grants and funding

311377/ERC_/European Research Council/International