Abortively Infected Astrocytes Appear To Represent the Main Source of Interferon Beta in the Virus-Infected Brain.

Abstract

Interferon beta (IFN-β) is a key component of cellular innate immunity in mammals, and it constitutes the first line of defense during viral infection. Studies with cultured cells previously showed that almost all nucleated cells are able to produce IFN-β to various extents, but information about the in vivo sources of IFN-β remains incomplete. By applying immunohistochemistry and employing conditional-reporter mice that express firefly luciferase under the control of the IFN-β promoter in either all or only distinct cell types, we found that astrocytes are the main producers of IFN-β after infection of the brain with diverse neurotropic viruses, including rabies virus, Theiler's murine encephalomyelitis virus, and vesicular stomatitis virus. Analysis of a panel of knockout mouse strains revealed that sensing of viral components via both RIG-I-like helicases and Toll-like receptors contributes to IFN induction in the infected brain. A genetic approach to permanently mark rabies virus-infected cells in the brain showed that a substantial number of astrocytes became labeled and, therefore, must have been infected by the virus at least transiently. Thus, our results strongly indicate that abortive viral infection of astrocytes can trigger pattern recognition receptor signaling events which result in secretion of IFN-β that confers antiviral protection. Previous work indicated that astrocytes are the main producers of IFN after viral infection of the central nervous system (CNS), but it remained unclear how astrocytes might sense those viruses which preferentially replicate in neurons. We have now shown that virus sensing by both RIG-I-like helicases and Toll-like receptors is involved. Our results further demonstrate that astrocytes get infected in a nonproductive manner under these conditions, indicating that abortive infection of astrocytes plays a previously unappreciated role in the innate antiviral defenses of the CNS.