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The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection

ABSTRACT: Goal: Determine the role of microglia in the antiviral response during neurotropic picornavirus infection of C57BL/6J and SJL/J mice and whether absence of microglia would affect CD4 and CD8 T cell functions. Methods: Brains from C57BL/6J and SJL/J mice treated with PLX5622 (to deplete microlgia) or control diet were harvested at 6 days post TMEV-infection. CD4+ T cells and CD8+ T cells were obtained using Easy Sep Mouse CD4+ T cell isolation Kit and Easy Sep Mouse CD8+ T cell isolation Kit (Stemcell). RNA was obtained using RNeasy (QIAGEN) and Illumina TruSeq stranded RNA Kit with Ribo-Zero Gold was then utilized to prepare cDNA library for RNA-seq. Results: Our results demonstrate strain-specific effects of the CSF1R-microglia axis in the context of neurotropic viral infection as well as inherent differences in microglial antigen presentation and subsequent T cell crosstalk that contribute to susceptibility to neurotropic picornavirus infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE160660 | GEO | 2021/05/10

REPOSITORIES: GEO

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The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection

Project description:The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection

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2015-06-22 | E-GEOD-66421 | biostudies-arrayexpress

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Project description:Acute influenza infection can be associated with neurological symptoms. Especially after the major pandemics reports about neuropsychiatric complications accumulated. However, the long-term consequences for the CNS of an infection with neurotropic but also non-neurotropic influenza A virus (IAV) variants remain largely elusive. The results presented here show that synapse loss in the hippocampus upon an infection with neurotropic H7N7 (rSC35M) as well as non-neurotropic H3N2 (maHK68) persists well beyond the acute phase of the disease. While hippocampal synapse number was significantly reduced 30 days post infection with both H7N7 and H3N2, full recovery could be observed 120 days post infection. Notably, infection with H1N1 (PR8) which was shown previously to affect spine number and hippocampus-dependent learning during the acute phase had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation and an impairment in spatial memory formation in the water maze indicating long-term inflammation induced functional and structural alterations in the hippocampus. Our data, therefore, provide evidence that while neuroinflammation induced by neurotropic H7N7 showed the strongest effect, also the systemic infection with a non-neurotropic influenza virus can result in long-term impairments in synapse number and function in the hippocampus. While young animals fully recover the outcome might be different in aged or otherwise compromised individuals, thereby directing future treatment strategies to pay attention to IAV induced processes of neuroinflammation.

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A functional conserved fragment of long intergenic non-coding RNA linc-AhRA negatively regulates innate antiviral response in microglia

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Whole mouse genome analysis of LCMV-specific CD4 and CD8 T cells throughout acute and chronic LCMV infection.

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Project description:Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill-defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus, strain JHMV), we show that depletion of microglia after clearance of virus infection resulted in impaired myelin repair and prolonged clinical disease. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Further, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial function could not be compensated by infiltrating macrophages. Together, these results demonstrate key roles for microglia in debris clearance and the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.

2020-02-07 | GSE144911 | GEO

Microglia influence host defense, disease, and repair following coronavirus infection of the central nervous system

Project description:The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells. Evaluation of spinal cord demyelination revealed a marked increase in white matter damage in PLX5622‐treated mice that corresponded with elevated expression of transcripts encoding disease‐associated proteins Osteopontin (Spp1), Apolipoprotein E (Apoe), and Triggering receptor expressed on myeloid cells 2 (Trem2) that were enriched within macrophages. In addition, PLX5622 treatment dampened expression of Cystatin F (Cst7), Insulin growth factor 1 (Igf1), and lipoprotein lipase (Lpl) within macrophage populations which have been implicated in promoting repair of damaged nerve tissue and this was associated with impaired remyelination. Collectively, these findings argue that microglia tailor the CNS microenvironment to enhance control of coronavirus replication as well as dampen the severity of demyelination and influence repair.

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