Targeted Killing Of Progenitor Cells Following TMEV Infection Leads To A Reduction In Oligodendrogenesis

The Theiler’s Murine Encephalomyelitis Virus (TMEV) serves to generate a chronic model of multiple sclerosis (MS) in susceptible SJL mice, but the mechanism mediating alterations in remyelination potential are not well understood. Neural progenitor cells (NPCs) were isolated from the telencephalon of naïve SJL mice and infected with TMEV. The in vitro survival of neural progenitor cells was significantly decreased by viral infection and upon differentiation, infected cultures produced significantly less oligodendrocytes and intriguingly more astrocytes and neurons than uninfected controls. We identified caspases 1 and 10 but not caspase 3 to be mediating decrease in cell survival. We found that TMEV infected NPCs, as well as astrocyte and oligodendrocyte progeny, however it did not infect neuron progeny. TMEV-infected oligodendrocytes were significantly stained by the TUNEL assay. Despite being infected by TMEV, astrocytes did not show TUNEL staining. Utilizing a co-culture system, TMEV-infected astrocytes were capable to induce cell death in naïve oligodendrocytes in an infection-independent manner. We found that TNF-alpha was released by TMEV-infected cells and mediated the by-stander effect on naïve oligodendrocytes. The neurogenic niche of the brain known as the subventricular zone (SVZ) was examined to determine what effects TMEV infection had on this area. A significant reduction in neural stem cells (NSCs) and oligodendrocyte progenitors cells (OPCs) was observed, as well as an increase in cell death as marked by TUNEL staining. This cell death was specific to NSCs and OPCs. We also observed an overall reduction in proliferation, which appears to be specific to NSCs and not OPCs. Overall, our findings illustrate a specific killing neural stem/progenitor cells and oligodendrocyte lineage following TMEV infection. This cell death may be TNF-alpha mediated and will ultimately lead to a reduction in oligodendrogenesis. Altered oligodendrogenesis may potential be contributing to the lack of remyelination seen in TMEV demyelinating disease, due to a reduction in the available pool of myelinating cells.