Abstract
Microglia become persistently infected during Theiler’s murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) of susceptible mice. We have previously shown that microglia infected with TMEV become activated through the innate immune receptors to express type I interferons, cytokines, and chemokines. Persistent TMEV infection in the CNS promotes chronic neuroinflammation and development of demyelinating disease similar to multiple sclerosis. In the current studies, we wanted to determine whether TMEV-infected microglia secrete exosomes which contribute to neuroinflammation in the CNS thus promoting the development of demyelinating disease. Exosomes are vesicles containing RNA, DNA, and proteins that are released from one cell and taken up by another cell to facilitate communication between cells. These studies isolated exosomes secreted by microglia during TMEV infection in vitro as well as exosomes secreted by microglia during early TMEV infection in mice. These studies show that microglia secrete exosomes during TMEV infection which contain the viral RNA coding region. The exosomes secreted by microglia during TMEV infection can be taken up by uninfected bystander cells, including CNS resident microglia, astrocytes, and neurons. The viral RNA in the exosomes can be transferred to the bystander cells. In addition, the bystander cells that took up these exosomes were activated through the innate immune response to express type I interferons, IFNα and IFNβ, pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and chemokines, CCL2. Most interestingly, exosomes secreted by microglia during early TMEV infection in mice activated an inflammatory response when transferred to the brains of naïve mice. These results show that exosomes secreted by microglia during early TMEV infection contain viral RNA and can activate uninfected bystander CNS cells to promote an inflammatory immune response. Thus, exosomes secreted by microglia during virus infection may promote viral persistence and neuroinflammation which contributes to the development of demyelinating disease.
Highlights
Theiler’s murine encephalomyelitis virus (TMEV) is a natural mouse pathogen that can establish a persistent virus infection in the central nervous system (CNS)
Microglia secrete exosomes under normal conditions, we wanted to determine whether exosomes secreted by microglia during TMEV infection have altered contents
The exosomes secreted by microglia during TMEV infection contain viral RNA which was transferred to uninfected CNS resident cells
Summary
Theiler’s murine encephalomyelitis virus (TMEV) is a natural mouse pathogen that can establish a persistent virus infection in the central nervous system (CNS). Our studies showed that exosomes secreted from microglia during TMEV infection do not contain TMEV viral particles but do contain the viral RNA genome which can be transferred to uninfected CNS resident cells such as microglia, astrocytes, and neurons These exosomes activated bystander CNS cells to express type I interferons and pro-inflammatory cytokines and chemokines through innate immune receptor recognition of the viral RNA. Exosomes secreted by microglia in the brain during early TMEV infection contained viral RNA which could be transferred to naïve mice activating an inflammatory immune response in the recipient mice
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