Exosomes secreted from virus- infected microglia can activate an inflammatory response in the central nervous system

Abstract

Abstract Exosomes are membrane-bound nanovesicles released from cells that can be taken up by other cells, thus mediating intercellular communication. Exosomes contain miRNA, mRNA, and proteins that are specific to the cells from which they were released. Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating disease is a mouse model for multiple sclerosis. 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 type I interferons, cytokines, chemokines, and effector molecules associated with development and progression of demyelinating disease. Next, we wanted to determine whether microglia infected with TMEV secrete exosomes and whether these exosomes could influence uninfected CNS resident cells, such as microglia, astrocytes, and neurons. Our studies show that exosomes secreted from virus-infected microglia contain viral RNA that can activate an innate immune response in uninfected bystander cells which leads to increased expression of pro-inflammatory cytokines. Most interestingly, exosomes secreted from microglia in the brain of TMEV- infected mice could be transferred to uninfected mice and activate an inflammatory immune response in the brain of uninfected mice. These results suggest that exosomes secreted by virus-infected microglia can activate the immune response in bystander uninfected cells which may contribute to the inflammatory response associated with demyelinating disease.