1. Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia
- Author
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Paul R. Kinchington, Phillip R. Kramer, Mingdi Zhang, William F. Goins, Benedikt B. Kaufer, Robert J. Visalli, Benjamin E. Warner, Michael B. Yee, and Rebecca S. Hornung
- Subjects
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 - 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., 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. more...
- Published
- 2021