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Review
. 2022 Nov 15:13:1044721.
doi: 10.3389/fimmu.2022.1044721. eCollection 2022.

Antiviral response within different cell types of the CNS

Affiliations
Review

Antiviral response within different cell types of the CNS

Zahra Telikani et al. Front Immunol. .

Abstract

The central nervous system (CNS) is a constitutive structure of various cell types conserved by anatomical barriers. Many of the major CNS cell-type populations distributed across the different brain regions are targets for several neurotropic viruses. Numerous studies have demonstrated that viral susceptibility within the CNS is not absolute and initiates a cell-type specific antiviral defence response. Neurons, astrocytes, and microglial cells are among the major resident cell populations within the CNS and are all equipped to sense viral infection and induce a relative antiviral response mostly through type I IFN production, however, not all these cell types adopt a similar antiviral strategy. Rising evidence has suggested a diversity regarding IFN production and responsiveness based on the cell type/sub type, regional distinction and cell`s developmental state which could shape distinct antiviral signatures. Among CNS resident cell types, neurons are of the highest priority to defend against the invading virus due to their poor renewable nature. Therefore, infected and uninfected glial cells tend to play more dominant antiviral roles during a viral infection and have been found to be the major CNS IFN producers. Alternatively, neuronal cells do play an active part during antiviral responses but may adopt differential strategies in addition to induction of a typical type I IFN response, to minimize the chance of cellular damage. Heterogeneity observed in neuronal IFN responsiveness may be partially explained by their altered ISGs and/or lower STATS expression levels, however, further in vivo studies are required to fully elucidate the specificity of the acquired antiviral responses by distinct CNS cell types.

Keywords: brain; central nervous system; innate immunity; interferon; virus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Main brain regions and cell types. (A) The brain is mainly composed of the cerebrum, cerebellum and the brain stem which are overlaid by the outermost layer called the cortex. Various cell types are distributed heterogeneously within different regions of the brain with some cell populations having higher or lower densities. (B) These brain structures are protected by anatomical restrictive barriers (choroid plexus, meninges, blood brain barrier (BBB), and olfactory epithelium) which create an interface between cerebrospinal fluid (CSF), blood and brain parenchyma and are also considered as entry portals for several viruses.
Figure 2
Figure 2
Differential type I IFN/IFNAR responses of major brain cell types. (A) Neurons, (B) Astrocytes and (C) Microglia are all equipped with machinery for viral sensing and can mount an antiviral response, particularly by inducing type I IFN production through various signaling pathways which intersect at activation of different protein kinases and IRF transcription factors, leading to induction of IFN gene transcription downstream. Although all tree cell types produce type I IFN, with astrocytes being major IFN-β producers, and microglia as the main source of IFN-α, there is a heterogenicity regarding neurons IFN responsiveness. Some neurons prefer autophagy rather than ISGs upregulation and induction of a typical antiviral state. This has been linked to lower STATs or basal ISGs levels in neurons compared to other cell types depending on cells developmental state, regional diversity, neuronal sub-types which may play definitive roles in shaping the outcome of the viral infection.
Figure 3
Figure 3
Regional diversity of innate immune responses within the brain. Coronally section of the human brain. Differential permissiveness of various cell types (Granule cell neurons, astrocytes and Microglia) situated in distinct anatomical locations (cortex, cerebrum and cerebellum) within the brain to several viruses; highlighting potent contribution of type I IFN mediated signaling pathways and over expression of relative ISGs.

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