Doctor of Philosophy

dissertationNeural precursor cell (NPC) transplantation has emerged as a therapeutic option to treat several neurological disorders. Intracranial infection of mice with the JHM strain of mouse hepatitis virus (JHMV) results in a chronic demyelinating disease and thus has been used as a model to study multiple sclerosis (MS). The cause of MS remains unknown but viruses have been attributed to trigger the disease in genetically susceptible individuals, making it imperative to study the remyelination potential of NPCs in a virally induced demyelinating disease. We have previously shown that engraftment of fetal derived GFP-NPCs in spinal cords of JHMV-infected mice with established demyelination results in remyelination and axonal sparing. We have previously demonstrated that transplanted GFP-NPCs are susceptible to JHMV-induced cell death. From a clinical standpoint, donor-specific induced pluripotent stem cells (iPSC)-derived NPCs may be preferable to avoid the use of immunosuppressive drugs. Therefore, we sought to investigate whether iPSC derived NPCs are functionally similar to fetal-derived NPCs and whether they are susceptible to JHMV infection in a preclinical setting. iPSCNPCs are similar to GFP-NPCs in functionality as they are able to differentiate into oligodendrocytes, astrocytes, and neurons. However, iPSC-NPCs express low levels of the viral receptor CEACAM1a, making them resistant to JHMV infection and viralinduced cytopathic effects. Activated microglia can prevent maturation of oligodendrocyte precursor cells (OPCs) to myelinating oligodendrocytes and promote oxidative damage by releasing nitric oxide. In the presence of environmental insults, activated microglia can release IL- 6, IL-23, IFN-γ and TNF-α, all of which can be neurotoxic and neuroinflammatory. Microglia can also contribute to adaptive immunity by presenting antigen to CD4+ and CD8+ T cells that have entered the central nervous system (CNS) in response to infection. In order to determine the contribution of microglia to disease progression in the JHMV model, we used colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in CNS of JHMV-infected mice. Microglia depletion results in increased viral titers, morbidity and, mortality and also modulates the immunological landscape of the CNS of JHMV-infected mice