Regionally distinct astrocyte interferon signaling promotes blood-brain barrier integrity and limits immunopathology during neurotropic viral infection

The role of astrocytes in innate immunity during viral infections of the central nervous system (CNS) remains to be fully elucidated. Here, we demonstrate that type I interferon (IFN) receptor (IFNAR) signaling in astrocytes regulates blood-brain barrier permeability and protects the cerebellum from infection and immunopathology. Mice with astrocytes lacking IFNAR signaling showed decreased survival after West Nile virus infection that was not due to expanded viral tropism or increased replication. Pattern recognition receptors and IFN-stimulated genes (ISGs) had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes compared to cerebral cortical astrocytes. Our data identify cerebellar astrocytes as key responders to viral infection and highlight distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS. Overall design: Primary human astrocytes were maintained on collagen-coated tissue culture plates in a complete astrocyte medium (ScienCell Laboratories) in 2% FBS. Prior to isolation of RNA, cells were treated for 4 hours with 10U/ml recombinant human IFN-ß or a PBS vehicle. Cells were then lysed in buffer RLT (Qiagen).