Exosomes secreted from microglia during chronic virus infection can induce demyelinating disease

Abstract

Abstract Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating disease is a murine model for multiple sclerosis (MS). TMEV persists in microglia and leads to development of chronic progressive demyelinating disease associated with an inflammatory immune response in the central nervous system (CNS) of susceptible mice. TMEV-infected microglia secrete innate immune cytokines, chemokines, and effector molecules associated with development and progression of demyelinating disease. Recently, we have found that TMEV-infected microglia secrete nanovesicles called exosomes that contain and transfer viral RNA to bystander cells in the CNS. Our present studies show that exosomes secreted by microglia during TMEV-induced demyelinating disease (63–98dpi) contain viral RNA/genome that can be taken up by other CNS resident cells, transferring the viral RNA. More importantly, these exosomes could induce the bystander CNS cells to express inflammatory cytokines and chemokines. When administered into naïve mice, exosomes secreted by microglia during TMEV-induced demyelinating disease promoted MS-like pathology including microglia activation and demyelination in the spinal cord. These results suggest that exosomes secreted by infected microglia may directly contribute to the development and progression of demyelinating disease.