In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-6), p. e1009689-
Abstract:
Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degron fused to ORF9p, a late structural protein that is required for virion assembly, induced nocifensive behaviors under both replication permissive and nonpermissive conditions, indicating that complete VZV replication is dispensable for the induction of hypersensitivity. This conclusion was confirmed by showing that a genetic deletion recombinant VZV lacking DNA packaging protein ORF54p still induced prolonged hypersensitivities in the rat. In contrast, VZV with a degron fused to the essential IE4 or IE63 proteins, which are involved in early gene regulation of expression, induced nocifensive behaviors only under replication permissive conditions, indicating importance of early gene expression events for induction of hypersensitivity. These data establish that while early viral gene expression is required for the development of nocifensive behaviors in the rat, complete replication is dispensable. We postulate this model reflects events leading to clinical PHN, in which a population of ganglionic neurons become abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009689
DOI:
10.1371/journal.ppat.1009689.g001
DOI:
10.1371/journal.ppat.1009689.g002
DOI:
10.1371/journal.ppat.1009689.g003
DOI:
10.1371/journal.ppat.1009689.g004
DOI:
10.1371/journal.ppat.1009689.g005
DOI:
10.1371/journal.ppat.1009689.g006
DOI:
10.1371/journal.ppat.1009689.g007
DOI:
10.1371/journal.ppat.1009689.g008
DOI:
10.1371/journal.ppat.1009689.g009
DOI:
10.1371/journal.ppat.1009689.g010
DOI:
10.1371/journal.ppat.1009689.g011
DOI:
10.1371/journal.ppat.1009689.t001
DOI:
10.1371/journal.ppat.1009689.t002
DOI:
10.1371/journal.ppat.1009689.s001
DOI:
10.1371/journal.ppat.1009689.s002
DOI:
10.1371/journal.ppat.1009689.s003
DOI:
10.1371/journal.ppat.1009689.s004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
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