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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Brain / cytology*
  • Brain / immunology
  • Cell Communication / immunology
  • Cells, Cultured
  • Chemokine CXCL10 / immunology*
  • Cognition Disorders / genetics*
  • Cognition Disorders / psychology
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • Endothelial Cells / immunology*
  • Endothelium / cytology
  • Endothelium / immunology
  • Epithelial Cells / immunology*
  • Epithelium / immunology
  • Illness Behavior / physiology*
  • Interferon Type I / therapeutic use
  • Interferon-Induced Helicase, IFIH1
  • Male
  • Mice
  • RNA, Double-Stranded / genetics
  • Receptor, Interferon alpha-beta / genetics*
  • Receptor, Interferon alpha-beta / immunology
  • Receptors, CXCR3 / immunology
  • Signal Transduction / immunology
  • Virus Diseases / immunology


  • Adaptor Proteins, Signal Transducing
  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Cxcr3 protein, mouse
  • IPS-1 protein, mouse
  • Ifnar1 protein, mouse
  • Interferon Type I
  • RNA, Double-Stranded
  • Receptors, CXCR3
  • Receptor, Interferon alpha-beta
  • Ddx58 protein, mouse
  • Ifih1 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1

Associated data

  • GEO/GSE74063