Exosomes Secreted by Microglia During Virus Infection in the Central Nervous System Activate an Inflammatory Response in Bystander Cells

Nhungoc Luong, Julie K. Olson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number661935
JournalFrontiers in Cell and Developmental Biology
Volume9
DOIs
StatePublished - Aug 13 2021

Bibliographical note

Funding Information:
We would like to thank Steven Penm and the staff at the University of Minnesota Characterization Facility, the Center for Mass Spectrometry, and the Nanoparticle Institute for their assistance in these studies. Funding. This work was supported by grants from University of Minnesota, College of Veterinary Medicine, Comparative Medicine. NL was supported by T32 grant DA007097.

Funding Information:
This work was supported by grants from University of Minnesota, College of Veterinary Medicine, Comparative Medicine. NL was supported by T32 grant DA007097.

Publisher Copyright:
© Copyright © 2021 Luong and Olson.

Keywords

  • demyelinating disease
  • exosome
  • microglia
  • neuroinflammation
  • virus infection

PubMed: MeSH publication types

  • Journal Article

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