Luong, Nhungoc2021-06-292021-06-292020-09https://hdl.handle.net/11299/220590University of Minnesota Ph.D. dissertation. September 2020. Major: Comparative and Molecular Biosciences. Advisor: Julie Olson. 1 computer file (PDF); xii, 137 pages.Multiple sclerosis (MS) is a chronic autoimmune-mediated demyelinating disease that affects more than 2.3 million people worldwide, especially young adults. The etiology is unknown, and effective treatments are unavailable. Viral infection(s) has been postulated to play a critical role in the initiation and progression of MS. My study utilizes a mouse model called Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) to better understand human MS. In TMEV-IDD, microglia, a resident macrophage in the central nervous system (CNS), are persistently infected with TMEV. As a result, the infected microglia produce an innate immune response that has been shown to contribute to bystander damage, bystander activation, and inflammation in the CNS, ultimately leading to demyelination. My central hypothesis is that exosomes secreted by microglia during TMEV infection may play an important role in sustaining persistence of virus and inflammation in the CNS, contributing to the development of demyelinating disease. We found that exosomes secreted by microglia during the acute phase (2 days post infection, dpi) and chronic phase (starting at 63dpi) of TMEV infection have altered surface markers and importantly, contain viral RNA/genome. We discovered that these exosomes are able to transfer viral RNA to uninfected CNS and infiltrating bystander cells to activate an innate immune response including expression of type I IFNs, pro-inflammatory cytokines, chemokines, and effector molecules. This activation was prominently triggered by the recognition viral RNA in exosomes by innate immune receptors. Naïve mice injected with exosomes secreted by microglia during TMEV infection showed microglia activation, neuroinflammation, and demyelination. In summary, these findings shed light on the role of exosomes in maintaining viral persistence and sustaining inflammation which are crucial in the development of virus-induced demyelinating disease in mice, and possibly human MS. The knowledge from this work may allow for identification of new therapeutic targets or disease-modifying strategies to treat demyelinating disease in human MS.enThesis or Dissertation