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microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease

Ana Lis Moyano1, Jeffrey Steplowski1, Haibo Wang2

  • 1Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|February 14, 2018
PubMed

Insights

MicroRNA-219 (miR-219) loss exacerbates Theiler's murine encephalomyelitis virus (TMEV) infection. Restoring miR-219 reduces neuroinflammation and viral load by impacting cholesterol biosynthesis, offering a potential therapeutic strategy for demyelinating diseases.

Area of Science:

  • Neuroimmunology
  • Virology
  • Molecular Biology

Background:

  • Theiler's murine encephalomyelitis virus (TMEV) infection causes demyelinating disease in the central nervous system.
  • MicroRNAs (miRs) play crucial roles in regulating gene expression and cellular processes, including myelin repair and immune responses.
  • miR-219 is a key regulator of myelin assembly and repair, but its role in TMEV-induced demyelination is not fully understood.

Purpose of the Study:

  • To investigate the role of miR-219 in TMEV-induced demyelinating disease.
  • To explore the therapeutic potential of restoring miR-219 expression in TMEV infection.
  • To elucidate the molecular mechanisms by which miR-219 exerts its effects.

Main Methods:

  • Analysis of miR expression in the central nervous system white matter of TMEV-infected SJL mice.
  • Intranasal administration of a synthetic miR-219 mimic before disease onset.
  • RNA sequencing of host lesions to identify miR-219-regulated genes.
  • Assessment of clinical disease, neurogliosis, motor function, and sensorimotor function.
  • Evaluation of cholesterol biosynthesis in infected mice and glial precursor cells.

Main Results:

  • TMEV infection led to a significant reduction of miR-219 in the central nervous system.
  • Restoration of miR-219 ameliorated clinical disease, reduced neurogliosis, and partially recovered motor function.
  • miR-219 negatively regulated proinflammatory cytokines and viral RNA replication.
  • miR-219 downregulated genes involved in cholesterol biosynthesis (Cyp51 and Srebf1), reducing cholesterol production.
  • Interference with cholesterol biosynthesis by miR-219 exhibited anti-inflammatory and anti-viral effects, inhibiting viral RNA replication.

Conclusions:

  • miR-219 plays a protective role in TMEV-induced demyelinating disease.
  • Restoring miR-219 expression is a potential therapeutic strategy for TMEV infection.
  • miR-219 exerts its protective effects through anti-inflammatory and anti-viral mechanisms, partly by modulating cholesterol biosynthesis.
Keywords:
anti-viralcholesterolmiRNA-219microgliamyelinoligodendrocytesvirus-induced demyelination

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