Defensive Perimeter in the Central Nervous System: Predominance of Astrocytes and Astrogliosis during Recovery from Varicella-Zoster Virus Encephalitis

Varicella-zoster virus (VZV) is a highly neurotropic virus that can cause infections in both the peripheral nervous system and the central nervous system. Several studies of VZV reactivation in the peripheral nervous system (herpes zoster) have been published, while exceedingly few investigations ha...

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Bibliographic Details
Published in:Journal of virology 2016-01, Vol.90 (1), p.379-391
Main Authors: Carpenter, John E, Clayton, Amy C, Halling, Kevin C, Bonthius, Daniel J, Buckingham, Erin M, Jackson, Wallen, Dotzler, Steven M, Card, J Patrick, Enquist, Lynn W, Grose, Charles
Format: Article
Language:English
Subjects:
Animals
Astrocytes - immunology
Astrocytes - virology
Disease Models, Animal
Encephalitis, Varicella Zoster - immunology
Encephalitis, Varicella Zoster - pathology
Encephalitis, Varicella Zoster - virology
Giant Cells - pathology
Giant Cells - virology
Gliosis - immunology
Gliosis - pathology
Herpesvirus 1, Suid
Herpesvirus 3, Human - immunology
Humans
Male
Pathogenesis and Immunity
Pseudorabies - immunology
Pseudorabies - pathology
Pseudorabies - virology
Pseudorabies virus
Rats, Sprague-Dawley
Temporal Lobe - pathology
Temporal Lobe - virology
Varicella-zoster virus
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Summary:Varicella-zoster virus (VZV) is a highly neurotropic virus that can cause infections in both the peripheral nervous system and the central nervous system. Several studies of VZV reactivation in the peripheral nervous system (herpes zoster) have been published, while exceedingly few investigations have been carried out in a human brain. Notably, there is no animal model for VZV infection of the central nervous system. In this report, we characterized the cellular environment in the temporal lobe of a human subject who recovered from focal VZV encephalitis. The approach included not only VZV DNA/RNA analyses but also a delineation of infected cell types (neurons, microglia, oligodendrocytes, and astrocytes). The average VZV genome copy number per cell was 5. Several VZV regulatory and structural gene transcripts and products were detected. When colocalization studies were performed to determine which cell types harbored the viral proteins, the majority of infected cells were astrocytes, including aggregates of astrocytes. Evidence of syncytium formation within the aggregates included the continuity of cytoplasm positive for the VZV glycoprotein H (gH) fusion-complex protein within a cellular profile with as many as 80 distinct nuclei. As with other causes of brain injury, these results suggested that astrocytes likely formed a defensive perimeter around foci of VZV infection (astrogliosis). Because of the rarity of brain samples from living humans with VZV encephalitis, we compared our VZV results with those found in a rat encephalitis model following infection with the closely related pseudorabies virus and observed similar perimeters of gliosis. Investigations of VZV-infected human brain from living immunocompetent human subjects are exceedingly rare. Therefore, much of our knowledge of VZV neuropathogenesis is gained from studies of VZV-infected brains obtained at autopsy from immunocompromised patients. These are not optimal samples with which to investigate a response by a human host to VZV infection. In this report, we examined both flash-frozen and paraffin-embedded formalin-fixed brain tissue of an otherwise healthy young male with focal VZV encephalitis, most likely acquired from VZV reactivation in the trigeminal ganglion. Of note, the cellular response to VZV infection mimicked the response to other causes of trauma to the brain, namely, an ingress of astrocytes and astrogliosis around an infectious focus. Many of the astrocytes themselves were in
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.02389-15