Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.
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.
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Thomas
T
Blank
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.
Claudia N
CN
Detje
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Alena
A
Spieß
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Nora
N
Hagemeyer
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Stefanie M
SM
Brendecke
Oscar Langendorff Institute of Physiology, University of Rostock, 18057 Rostock, Germany.
Jakob
J
Wolfart
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Ori
O
Staszewski
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Tanja
T
Zöller
Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
Ismini
I
Papageorgiou
Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
Justus
J
Schneider
Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany.
Ricardo
R
Paricio-Montesinos
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.
Ulrich L M
UL
Eisel
Ruhr University Bochum, Medical Faculty, Department Neurophysiology, 44780 Bochum, Germany.
Denise
D
Manahan-Vaughan
Ruhr University Bochum, Medical Faculty, Department Neurophysiology, 44780 Bochum, Germany.
Stephan
S
Jansen
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.
Stefan
S
Lienenklaus
Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bao
B
Lu
Department of Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
Yumiko
Y
Imai
Department of Neurology, Universitätsklinikum Bonn, 53105 Bonn, Germany.
Marcus
M
Müller
Portland, Oregon, 97201, USA.
Susan E
SE
Goelz
Biogen Inc., Cambridge, MA 02142, USA.
Darren P
DP
Baker
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23538 Lübeck, Germany.
Markus
M
Schwaninger
Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
Oliver
O
Kann
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.
Mathias
M
Heikenwalder
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.
Ulrich
U
Kalinke
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.
Marco
M
Prinz
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology*; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology*; D004727:Endothelium / Q000166:cytology / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology*; D004848:Epithelium / Q000276:immunology; D055809:Illness Behavior / Q000502:physiology*; D007370:Interferon Type I / Q000627:therapeutic use; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D051379:Mice; D012330:RNA, Double-Stranded / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics* / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D054357:Chemokine CXCL10; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D012330:RNA, Double-Stranded; D053633:Receptor, Interferon alpha-beta; D054367:Receptors, CXCR3; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; C512612:MAVS protein, mouse; C508032:Ifnar1 protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse
CXCL10; CXCR3; IFN; IFNAR1; IPS-1; MAVS; behavior; brain; depression; endothelia; epithelia; influenza; neurons; signal transduction; type I interferon; virus infection