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

Thomas Blank; Claudia N. Detje; Alena Spieß; Nora Hagemeyer; Stefanie M. Brendecke; Jakob Wolfart; Ori Staszewski; Tanja Zöller; Ismini Papageorgiou; Justus Schneider; Ricardo Paricio-Montesinos; Ulrich L.M. Eisel; Denise Manahan-Vaughan; Stephan Jansen; Stefan Lienenklaus; Bao Lu; Yumiko Imai; Marcus Müller; Susan E. Goelz; Darren P. Baker; Markus Schwaninger; Oliver Kann; Mathias Heikenwalder; Ulrich Kalinke; Marco Prinz

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

Thomas Blank, Claudia N. Detje, Alena Spieß, Nora Hagemeyer, Stefanie M. Brendecke, Jakob Wolfart, Ori Staszewski, Tanja Zöller, Ismini Papageorgiou, Justus Schneider, Ricardo Paricio-Montesinos, Ulrich L.M. Eisel, Denise Manahan-Vaughan, Stephan Jansen, Stefan Lienenklaus, Bao Lu, Yumiko Imai, Marcus Müller, Susan E. Goelz, Darren P. BakerMarkus Schwaninger, Oliver Kann, Mathias Heikenwalder, Ulrich Kalinke, Marco Prinz^*

^*Corresponding author for this work

Institute of Experimental and Clinical Pharmacology and Toxicology

137 Citations (Scopus)

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.

Original language	English
Journal	Immunity
Volume	44
Issue number	4
Pages (from-to)	901-912
Number of pages	12
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2016.04.005
Publication status	Published - 19.04.2016

Funding

We thank Maria Oberle, Margarethe Ditter, and Christine El Gaz for excellent technical assistance and Silke Dirken for animal care. M.P. was supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the competence network of neurodegenerative disorders (KNDD), the DFG (PR 577/8-1, Reinhart-Koselleck grant), the ERA-Net NEURON initiative “NEURO-IFN,” and the Gemeinnützige Hertie Foundation (GHST). T.B. was supported by the Marie Curie Integration Grant project N° 248033- MBfUSEDIT submitted under the Call FP7-PEOPLE-2009-RG and the DFG (BL 1153/1-1). D.M.-V. was supported by the SFB 874/B1. U.K. was supported by the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany, and the SFB 854 (TP B15 to U.K.) of the German Research Council. Mouse IFN-β was supplied by Biogen Inc. D.P.B. is an employee of Biogen and owns company stock.

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Blank, T., Detje, C. N., Spieß, A., Hagemeyer, N., Brendecke, S. M., Wolfart, J., Staszewski, O., Zöller, T., Papageorgiou, I., Schneider, J., Paricio-Montesinos, R., Eisel, U. L. M., Manahan-Vaughan, D., Jansen, S., Lienenklaus, S., Lu, B., Imai, Y., Müller, M., Goelz, S. E., ... Prinz, M. (2016). Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment. Immunity, 44(4), 901-912. https://doi.org/10.1016/j.immuni.2016.04.005

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title = "Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment",

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.",

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Blank, T, Detje, CN, Spieß, A, Hagemeyer, N, Brendecke, SM, Wolfart, J, Staszewski, O, Zöller, T, Papageorgiou, I, Schneider, J, Paricio-Montesinos, R, Eisel, ULM, Manahan-Vaughan, D, Jansen, S, Lienenklaus, S, Lu, B, Imai, Y, Müller, M, Goelz, SE, Baker, DP, Schwaninger, M, Kann, O, Heikenwalder, M, Kalinke, U & Prinz, M 2016, 'Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment', Immunity, vol. 44, no. 4, pp. 901-912. https://doi.org/10.1016/j.immuni.2016.04.005

TY - JOUR

T1 - Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

AU - Blank, Thomas

AU - Detje, Claudia N.

AU - Spieß, Alena

AU - Hagemeyer, Nora

AU - Brendecke, Stefanie M.

AU - Wolfart, Jakob

AU - Staszewski, Ori

AU - Zöller, Tanja

AU - Papageorgiou, Ismini

AU - Schneider, Justus

AU - Paricio-Montesinos, Ricardo

AU - Eisel, Ulrich L.M.

AU - Manahan-Vaughan, Denise

AU - Jansen, Stephan

AU - Lienenklaus, Stefan

AU - Lu, Bao

AU - Imai, Yumiko

AU - Müller, Marcus

AU - Goelz, Susan E.

AU - Baker, Darren P.

AU - Schwaninger, Markus

AU - Kann, Oliver

AU - Heikenwalder, Mathias

AU - Kalinke, Ulrich

AU - Prinz, Marco

PY - 2016/4/19

Y1 - 2016/4/19

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84964330538

U2 - 10.1016/j.immuni.2016.04.005

DO - 10.1016/j.immuni.2016.04.005

M3 - Journal articles

C2 - 27096319

AN - SCOPUS:84964330538

SN - 1074-7613

VL - 44

SP - 901

EP - 912

JO - Immunity

JF - Immunity

IS - 4

ER -

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

Abstract

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Research Areas and Centers

UN SDGs

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