Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Mangale V

PROVIDER: S-EPMC7280614 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mangale Vrushali V Syage Amber R AR Ekiz H Atakan HA Skinner Dominic D DD Cheng Yuting Y Stone Colleen L CL Brown R Marshall RM O'Connell Ryan M RM Green Kim N KN Lane Thomas E TE

Glia 20200525 11

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 correlat ...[more]

PMID: 32449994

Similar Datasets

Project description:Background: Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. Methods: Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Immune cell infiltration into the brain and spinal cord was determined by flow cytometry. Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and remyelination evaluated by electron microscopy (EM) and calculation of g-ratios. Immune cell infiltration into the CNS and microglia activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNAseq). Results: JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells and monocytes/macrophages into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with amplified demyelination and impaired remyelination. Single-cell RNA-seq of CD45+ cells enriched from spinal cords of infected Cst7-/- and control mice at day 21 post-infection (p.i.) revealed enhanced expression of transcripts encoding macrophage chemoattractant, Ccl2, and T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) transcripts and activation markers in CD8+ T cells from Cst7-/- mice compared to controls. Conclusions: Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of macrophage and T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the theory that one mechanism by which cystatin F affects chronic disease in mice persistently infected with JHMV is through regulating expression of pro-inflammatory molecules that impact neuroinflammation and neurologic disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets