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Intranasal therapy with miRNA-219 reduces viral load and encephalomyelitis in the TMEV model of multiple sclerosis

ABSTRACT: Purpose: RNA sequencing of spinal cord following intranasal administration of miRNA-219 in Theiler’s murine encephalomyelitis virus (TMEV) model of multiple sclerosis Methods: RNA isolated from spinal cords was analyzed by Next-Generation RNA Sequencing (Illumina) Results: Here, we analyzed the therapeutic effects of miR-219 in a virus-induced demyelinating model. Following intranasal administration of miR-219 in TMEV-infected mice, we found significant reduction of clinical signs, virus persistence (virus genome copy numbers), neuroglia activation, proinflammatory cytokine levels, and demyelination. RNA sequencing of expressed host genes demonstrated that miR-219 potentiates transcriptional changes in cholesterol-related genes, leading to reduced levels of this lipid. Conclusions: Since virus replication relies on hijacking cholesterol biosynthesis and trafficking of host cell endogenous pools as well as remodeling intracellular membranes, i.e., the virus replication organelles or viroplasm, treatment with miR-219 may interfere with virus RNA replication through downregulation of cholesterol synthesis. Our findings show that miR-219 administration lessens pathological changes by reducing the CNS virus loads and favoring myelin repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE107091 | GEO | 2020/11/16

REPOSITORIES: GEO

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Project description:Theiler’s murine encephalomyelitis virus (TMEV) induces different diseases in the central nervous system (CNS) and heart, depending on the mouse strains and time course, where cytokines play a key role for viral clearance and immune-mediated pathology (immunopathology). In SJL/J mice, TMEV infection causes chronic TMEV-induced demyelinating disease (TMEV-IDD) in the spinal cord around 1 month post infection (p.i.). Unlike other immunopathology models, both pro-inflammatory and anti-inflammatory cytokines can play dual roles in TMEV-IDD. Pro-inflammatory cytokines play a beneficial role in viral clearance while they also play a detrimental role in immune-mediated demyelination. Anti-inflammatory cytokines suppress not only protective anti-viral immune responses but also detrimental autoreactive immune responses. On the other hand, in C3H mice, TMEV infection induces a non-CNS disease, myocarditis, with three phases: phase I, viral pathology with interferon and chemokine responses; phase II, immunopathology mediated by acquired immune responses; and phase III, cardiac fibrosis. Although the precise mechanism how a single virus, TMEV, induces the distinct diseases in different organs is unclear, principal component analysis (PCA) of transcriptome data allows us to identify the key factors contributing to distinct immunopathology. The PCA demonstrated that in vitro infection of a cardiomyocyte cell line could reproduce the transcriptome profile of phase I in TMEV-induced myocarditis; distinct interferon/chemokine-related responses were induced in vitro in infected cardiomyocytes, but not in infected neuronal cells. In addition, the PCA of in vivo CNS transcriptome data showed that decreased lymphatic marker expression was associated with inflammation in TMEV infection. Here, dysfunction of lymphatic vessels may contribute to immunopathology by delaying clearance of cytokines and immune cells from the inflammatory site, although this might confine the virus at the site, preventing virus spread via lymphatic vessels. On the other hand, in the heart, dysfunction of lymphatics was associated with reduced lymphatic muscle contractility by pro-inflammatory cytokines. Therefore, TMEV infection could induce different cytokine expressions as well as lymphatic vessel dysfunction by the distinct mechanism between the CNS and heart, which might contribute to organ-specific immunopathology.

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Intranasal therapy with miRNA-219 reduces viral load and encephalomyelitis in the TMEV model of multiple sclerosis

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