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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 8

Altered T cell response in the brains of microglia-depleted mice.

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Altered T cell response in the brains of microglia-depleted mice.
Mice w...
Mice were treated with PLX5622 for 7 days prior to viral inoculation. In A–I and L, mice were inoculated via intracranial injection with MHV. In A–I, immune cells in the brain were assessed by flow cytometry on day 7 p.i. Frequency and number of CD8+ T cells (A), CD4+ T cells (B), and Tregs (C) in the brain. (D) Virus-specific CD8+ T cell frequency and number were determined by IFN-γ ICS after stimulation with S510 peptide. (E) Virus-specific CD4+ T cell frequency and number were determined by IFN-γ ICS after stimulation with M133 peptide. IL-10 (F and I) and TNF (G and H) expression in virus-specific (IFN-γ+) CD4+ and CD8+ T cells, respectively. (J and K) Virus-specific CD4+ and CD8 + T cells in the spleen on day 7 after i.p. injection of rJ. (L) Survival of Rag1–/– mice. Data indicate the mean ± SEM and represent combined data from 3 to 5 independent experiments, with a combined total of 9 to 17 mice per group. Statistical significance determined using Mann-Whitney U tests. *P < 0.05, **P < 0.01, and ***P < 0.001. The significance in differences in survival curves was assessed by log-rank test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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