@article{9c3f95d6d96e4437ab2958a839275d1c,
title = "Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection",
abstract = "Type I IFNs promote cellular responses to viruses, and IFN receptor (IFNAR) signaling regulates the responses of endothelial cells of the blood-brain barrier (BBB) during neurotropic viral infection. However, the role of astrocytes in innate immune responses of the BBB during viral infection of the CNS remains to be fully elucidated. Here, we have demonstrated that type I IFNAR signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Mice with astrocyte-specific loss of IFNAR signaling showed decreased survival after West Nile virus infection. Accelerated mortality was not due to expanded viral tropism or increased replication. Rather, viral entry increased specifically in the hindbrain of IFNAR-deficient mice, suggesting that IFNAR signaling critically regulates BBB permeability in this brain region. Pattern recognition receptors and IFN-stimulated genes had higher basal and IFN-induced expression in human and mouse cerebellar astrocytes than did cerebral cortical astrocytes, suggesting that IFNAR signaling has brain region-specific roles in CNS immune responses. Taken together, our data identify cerebellar astrocytes as key responders to viral infection and highlight the existence of distinct innate immune programs in astrocytes from evolutionarily disparate regions of the CNS.",
author = "Daniels, {Brian P.} and Harsha Jujjavarapu and Durrant, {Douglas M.} and Williams, {Jessica L.} and Green, {Richard R.} and White, {James P.} and Lazear, {Helen M.} and Michael Gale and Diamond, {Michael S.} and Klein, {Robyn S.}",
note = "Funding Information: Acknowledgments We thank Denise Dorsey, Qingping Wu, and Matthew Cain for their technical assistance (Washington University School of Medicine, St. Louis, MO, USA). We also thank the University of Washington's Center for Innate Immunity and Immune Disease Immuno-Informatics core group for their bioinformatics support. This work was supported by NIH grants U19 AI083019 (to RSK, MSD, and MG), R01 NS052632 (to RSK), and R01 AI104002 (to MG). BPD was supported by a National Science Foundation Graduate Research Fellowship (DGE-1143954) and an NIH NRSA fellowship (F31-NS07866). JLW was supported by a postdoctoral fellowship from the National Multiple Sclerosis Society. JPW was supported by an NIH NRSA fellowship (F32-AI112274). Experimental support was provided by the Speed Congenics Facility of the Rheumatic Diseases Core Center (Washington University School of Medicine, St. Louis, MO, USA). Research reported in this article was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH, under award number P30AR048335. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.",
year = "2017",
month = mar,
day = "1",
doi = "10.1172/JCI88720",
language = "English",
volume = "127",
pages = "843--856",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
number = "3",
}