Microglia secrete exosomes during persistent virus infection of the central nervous system that promote demyelinating disease

Abstract

Abstract Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a mouse model for multiple sclerosis (MS). TMEV infection of susceptible mice leads to a persistent viral infection of microglia in the central nervous system (CNS) which contributes to the development of a chronic progressive demyelinating disease associated with an inflammatory immune response. We have previously shown that TMEV infection of microglia activates an innate immune response with expression of cytokines, chemokines, and effector molecules associated with development and progression of demyelinating disease. Recently, we have shown that TMEV-infected microglia secrete exosomes, which are membrane-bound nanovesicles (60–150 nm). Exosomes contain and facilitate intercellular transfer of a wide variety of materials, including miRNA, mRNA, and proteins. We wanted to determine whether the exosomes secreted by TMEV-infected microglia can be taken up by other CNS resident cells and contribute to the persistent virus infection and inflammatory response during demyelinating disease. Our studies showed that exosomes secreted from microglia during TMEV-induced demyelinating disease (63–98 dpi) contain viral RNA/genome and can be taken up by other CNS resident cells. These exosomes activated the CNS resident cells to express inflammatory cytokines and chemokines. More importantly, the exosomes secreted by microglia during TMEV-induced demyelinating disease could induce MS-like pathology including neuroinflammation and demyelination in naïve mice. These results suggest that exosomes secreted by infected microglia may directly contribute to the development and progression of demyelinating disease.