Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia

Autor: Paul R. Kinchington, Phillip R. Kramer, Mingdi Zhang, William F. Goins, Benedikt B. Kaufer, Robert J. Visalli, Benjamin E. Warner, Michael B. Yee, Rebecca S. Hornung
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Herpesvirus 3
Human
viruses
Neuralgia
Postherpetic
Gene Expression
medicine.disease_cause
Virus Replication
Biochemistry
Nervous System
Rats
Sprague-Dawley
0302 clinical medicine
Medicine and Health Sciences
Biology (General)
Nerve Tissue
Regulation of gene expression
Neurons
Mammals
education.field_of_study
virus diseases
Eukaryota
Animal Models
Nucleic acids
Experimental Organism Systems
Virion assembly
Vertebrates
Anatomy
Research Article
QH301-705.5
Population
Immunology
Pain
Molecular Probe Techniques
Biology
DNA replication
Research and Analysis Methods
Rodents
Microbiology
Virus
03 medical and health sciences
Model Organisms
Signs and Symptoms
Virology
medicine
Hypersensitivity
Genetics
Animals
education
Molecular Biology Techniques
Molecular Biology
Postherpetic neuralgia
Varicella zoster virus
Organisms
Biology and Life Sciences
500 Naturwissenschaften und Mathematik::570 Biowissenschaften
Biologie::570 Biowissenschaften
Biologie
DNA
RC581-607
medicine.disease
Viral Replication
Probe Hybridization
Rats
Disease Models
Animal
030104 developmental biology
Biological Tissue
Viral replication
Varicella Zoster Virus Infection
Amniotes
Animal Studies
Parasitology
Clinical Immunology
Ganglia
Immunologic diseases. Allergy
Clinical Medicine
Zoology
030217 neurology & neurosurgery
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 17, Iss 7, p e1009689 (2021)
ISSN: 1553-7374
Popis: 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.
Author summary Acute and chronic pain are common complications of herpes zoster, but the mechanisms underlying the transition to chronic pain states remain poorly understood. Varicella-zoster virus (VZV)-inoculated rats develop persistent behaviors that indicate the development of prolonged hypersensitivity that may model postherpetic neuralgia (PHN) seen in the clinic. To address the requirements of viral gene expression and replication for the induction of pain, we developed mutant VZV and applied them to rat models of PHN. Our results reveal the production of essential VZV regulatory proteins is required to induce nocifensive behaviors, but that full productive virus replication is dispensable. These data suggest a mechanism for pain induction that involves the early expression of VZV regulatory proteins in abortively infected neurons after herpes zoster that may cause aberrant host pain signaling and PHN.
Databáze: OpenAIRE
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