Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

Abstract

A variety of viruses can induce central nervous system (CNS) infections and neurological diseases, although the incidence is rare. Similar to peripheral infections, IFNα/β induction and signaling constitutes a first line of defense to limit virus dissemination. However, CNS-resident cells differ widely in their repertoire and magnitude of both basal and inducible components in the IFNα/β pathway. While microglia as resident myeloid cells have been implicated as prominent sentinels of CNS invading pathogens or insults, astrocytes are emerging as key responders to many neurotropic RNA virus infections. Focusing on RNA viruses, this review discusses the role of astrocytes as IFNα/β inducers and responders and touches on the role of IFNα/β receptor signaling in regulating myeloid cell activation and IFNγ responsiveness. A summary picture emerges implicating IFNα/β not only as key in establishing the classical "antiviral" state, but also orchestrating cell mobility and IFNγ-mediated effector functions.

Keywords: IFN; IFN/; astrocytes; viral encephalitis.

FIG. 1.

The interdependence of CNS cells in optimizing protective IFNα/β function. In many neurotropic virus infections, microglia and astrocytes induce initial IFNα/β and are the main sources of IFNβ, despite their prominent neuronal tropism. Locally induced IFNα/β binds to IFNAR on both infected and uninfected cell types, thereby activating an IFNAR signaling cascade, which induces expression of ISGs and amplifies IFNα/β responses. IFNAR signaling specifically on astrocytes promotes BBB integrity, and serves to limit virus replication, thereby restricting infection of other susceptible cells types and stemming spread throughout the CNS. Even focal IFNα/β restricted to the site of infection suffices to activate ISGs at distal sites to alert other connected CNS regions of a potential viral threat. Finally sustained IFNα/β can alter T cell-induced IFNγ function. BBB, blood–brain barrier; CNS, central nervous system; IFNAR, IFNα/β receptor; IFNGR, IFNγ receptor; ISG, IFN-stimulated gene.