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Microglia are required for protection against lethal coronavirus encephalitis in mice
D. Lori Wheeler, … , David K. Meyerholz, Stanley Perlman
D. Lori Wheeler, … , David K. Meyerholz, Stanley Perlman
Published January 29, 2018
Citation Information: J Clin Invest. 2018;128(3):931-943. https://doi.org/10.1172/JCI97229.
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Research Article Immunology Virology

Microglia are required for protection against lethal coronavirus encephalitis in mice

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Abstract

Recent findings have highlighted the role of microglia in orchestrating normal development and refining neural network connectivity in the healthy CNS. Microglia are not only vital cells in maintaining CNS homeostasis, but also respond to injury, infection, and disease by undergoing proliferation and changes in transcription and morphology. A better understanding of the specific role of microglia in responding to viral infection is complicated by the presence of nonmicroglial myeloid cells with potentially overlapping function in the healthy brain and by the rapid infiltration of hematopoietic myeloid cells into the brain in diseased states. Here, we used an inhibitor of colony-stimulating factor 1 receptor (CSF1R) that depletes microglia to examine the specific roles of microglia in response to infection with the mouse hepatitis virus (MHV), a neurotropic coronavirus. Our results show that microglia were required during the early days after infection to limit MHV replication and subsequent morbidity and lethality. Additionally, microglia depletion resulted in ineffective T cell responses. These results reveal nonredundant, critical roles for microglia in the early innate and virus-specific T cell responses and for subsequent host protection from viral encephalitis.

Authors

D. Lori Wheeler, Alan Sariol, David K. Meyerholz, Stanley Perlman

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Figure 1

Microglia respond to CNS infection.

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Microglia respond to CNS infection.
(A) Olfactory bulb sections from CX3...
(A) Olfactory bulb sections from CX3CR1GFP/+ mice were immunostained for IBA1 and with DAPI nuclear stain at the indicated time points relative to infection. Images are representative of 3 mice per group. Scale bars: 100 μm. (B) Microglia from naive and day-4 p.i. brains were isolated by flow cytometry and subjected to microarray analysis. Heatmap shows the 595 differentially expressed genes and log2 expression values from blue to red. (C) Pathways most altered in microglia after infection as assessed by Ingenuity Pathway Analysis. Orange bars indicate pathway upregulation; blue bars indicate downregulation of the pathway. Gray bars indicate that no direction of pathway dysregulation was detected. (D) Fold change of selected differentially expressed genes in microglia after infection. Data in B–D were derived from 4 independent samples per group and were analyzed as described in Methods. dpi, days post infection.
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