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

MOYANO ANA LIS; STEPLOWSKI, JEFFREY; WANG, HAIBO; SON, KYUNG-NO; RAPOLTI, DIANA I.; MARSHALL, JEFFREY; ELACKATTU, VINCE; MARSHALL, MICHAEL S.; HEBERT, AMY K.; REITER, CORY R.; ULLOA, VIVIANA; PITUCH, KATARZYNA C.; GIVOGRI, MARIA I.; LU, Q. RICHARD; LIPTON, HOWARD L.; BONGARZONE, ERNESTO R.

Buenos Aires

Congreso; Role of Glia in health and Disease - ISN/IBRO/FONCYT; 2017

Analysis of miRNA expression in the central nervous system (CNS) white matter of SJL mice infected with the BeAn strain of Theiler?s murine encephalomyelitis virus (TMEV) revealed a significant reduction of miRNA-219 (miR-219), a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic had a beneficial effect on clinical disease, neurogliosis, and sensorimotor physiological function by negatively affecting proinflammatory cytokine production and viral RNA replication. Moreover, RNA sequencing analysis showed that miR-219 potentiates transcriptional changes in cholesterol-related genes, leading to lower levels of this lipid in vivo and in vitro. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA viral replication and are dependent upon endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis impacted viral RNA replication. These findings demonstrate that miR-219 exerts its beneficial effect on TMEV-induced demyelinating disease not only by promoting myelin repair, but also by reducing viral load in CNS infections.