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Immunity. 2016 Apr 19;44(4):901-12. doi: 10.1016/j.immuni.2016.04.005.

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Author information

1
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
2
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Medical School Hannover, 30625 Hannover, Germany.
3
Oscar Langendorff Institute of Physiology, University of Rostock, 18057 Rostock, Germany.
4
Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
5
Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, University of Groningen, and Department of Psychiatry, University Medical Center Groningen, 9700 Groningen, The Netherlands.
6
Ruhr University Bochum, Medical Faculty, Department Neurophysiology, 44780 Bochum, Germany.
7
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Medical School Hannover, 30625 Hannover, Germany; Institute for Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
8
Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
10
Department of Neurology, Universitätsklinikum Bonn, 53105 Bonn, Germany.
11
Portland, Oregon, 97201, USA.
12
Biogen Inc., Cambridge, MA 02142, USA.
13
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23538 Lübeck, Germany.
14
Institute of Virology, Technische Universität München/ Helmholtz-Zentrum München, 81756 München, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
15
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. Electronic address: marco.prinz@uniklinik-freiburg.de.

Abstract

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

KEYWORDS:

CXCL10; CXCR3; IFN; IFNAR1; IPS-1; MAVS; behavior; brain; depression; endothelia; epithelia; influenza; neurons; signal transduction; type I interferon; virus infection

PMID:
27096319
DOI:
10.1016/j.immuni.2016.04.005
[Indexed for MEDLINE]
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