Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection
Brian P. Daniels, … , Michael S. Diamond, Robyn S. Klein
Brian P. Daniels, … , Michael S. Diamond, Robyn S. Klein
Published January 30, 2017
Citation Information: J Clin Invest. 2017;127(3):843-856. https://doi.org/10.1172/JCI88720.
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Research Article Infectious disease

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.

Authors

Brian P. Daniels, Harsha Jujjavarapu, Douglas M. Durrant, Jessica L. Williams, Richard R. Green, James P. White, Helen M. Lazear, Michael Gale Jr., Michael S. Diamond, Robyn S. Klein

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Figure 6

Survival, immune infiltrates, and immunopathology following pharmacological blockade of VLA-4.

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Survival, immune infiltrates, and immunopathology following pharmacologi...
(A–D) Mice were inoculated via an intracerebellar route with WNV. Infected mice in all experiments were treated i.p. with 10 mg/kg BIO5192, a small-molecule VLA-4 antagonist, or vehicle solution beginning on day 4 after infection. (A) Survival was monitored daily following infection (n = 7 mice/group). (B) Flow cytometric analysis of immune infiltrates in the cerebellum on day 6 after infection (n = 4 mice/group) (C) Immunohistochemical detection of TUNEL+ neurons (NeuN, left) and astrocytes (S100-β, right) in cerebellar granule cell layers of infected mice on day 6 after infection. Scale bar: 50 μm. (D) Quantification of dead and dying neurons (left panel) or astrocytes (right panel), generated by counting cells double positive for TUNEL and the appropriate cell marker (depicted in pixel masked images to the right of merged RGB images). Data are taken from counting 4 images from 2 nonserial sections per mouse (5 mice/group). Counts for each image were normalized to the total area of granule cell layer present per high-power field. All data represent pooled values from 2 independent experiments. *P < 0.05 , **P < 0.01, and ***P < 0.001, by log-rank test (A) or 2-way ANOVA (B and D).