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Review
. 2023 Apr;71(4):803-818.
doi: 10.1002/glia.24294. Epub 2022 Nov 5.

The multitaskers of the brain: Glial responses to viral infections and associated post-infectious neurologic sequelae

Veronica A Davé  1 , Robyn S Klein  1
Affiliations
Review

The multitaskers of the brain: Glial responses to viral infections and associated post-infectious neurologic sequelae

Veronica A Davé et al. Glia. 2023 Apr.

Abstract

Many viral infections cause acute and chronic neurologic diseases which can lead to degeneration of cortical functions. While neurotropic viruses that gain access to the central nervous system (CNS) may induce brain injury directly via infection of neurons or their supporting cells, they also alter brain function via indirect neuroimmune mechanisms that may disrupt the blood-brain barrier (BBB), eliminate synapses, and generate neurotoxic astrocytes and microglia that prevent recovery of neuronal circuits. Non-neuroinvasive, neurovirulent viruses may also trigger aberrant responses in glial cells, including those that interfere with motor and sensory behaviors, encoding of memories and executive function. Increasing evidence from human and animal studies indicate that neuroprotective antiviral responses that amplify levels of innate immune molecules dysregulate normal neuroimmune processes, even in the absence of neuroinvasion, which may persist after virus is cleared. In this review, we discuss how select emerging and re-emerging RNA viruses induce neuroimmunologic responses that lead to dysfunction of higher order processes including visuospatial recognition, learning and memory, and motor control. Identifying therapeutic targets that return the neuroimmune system to homeostasis is critical for preventing virus-induced neurodegenerative disorders.

Keywords: astrocyte; host-pathogen interactions; microglia; neuroimmunology; neurovirology.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Glia facilitate clearance of CNS viral infections, but also mediate neurologic damage.
During neuroinvasive and neurovirulent viral infections, glia perform functions that are essential to viral clearance and neurocognitive recovery, such as regulating the BBB, maintaining chemokine gradients, and phagocytosing debris. However, these responses can also damage neuronal tissue by promoting chronic inflammation, impeding neurogenesis, and pruning synapses.
Figure 2.
Figure 2.. Glia use distinct detection pathways to respond to different types of viral infection.
Viruses associated with neurocognitive sequelae may be gliatropic, neurotropic, neurovirulent, or some combination of each. Glia can recognize gliatropic viruses (left) via intracellular innate sensing receptors, such as endosomal Toll-like receptors or cytosolic pattern-recognition receptors that bind to viral nucleic acids. Infected glia can further amplify their innate immune response via autocrine cytokine signaling. Glia may recognize neurotropic viral infection (middle) via paracrine cytokine signaling. Infected neurons may also signal to glia via the release of damage-associated molecules such as chaperone proteins, host DNA, or ATP. Finally, glia may mediate neuroinflammation in response to neurovirulent viruses (right) via the sensing or translocation of viral particles or cytokines from the circulation. Hypoxia resulting from respiratory disease could amplify these signals via alterations to the blood-brain barrier.
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