Post-Herpetic Neuralgia (PHN) is a common and exceedingly painful complication of herpes zoster that is debilitating, intractable, long-lasting and difficult to treat. PHN increases dramatically with age, and is thus a disease of the elderly which may profoundly reduce the quality of life. Given the aging nature of our society, PHN will become an even more pressing public health concern. Zoster and PHN occur when the human herpesvirus, varicella-zoster virus (VZV), reactivates from a latent state that was established in the host sensory neurons during chickenpox. While viral replication induces nerve damage and inflammation to initiate pain, the mechanisms by which VZV causes persistent pain are not well understood. This project is directed to FOA PA-07-282, and will center on a new clinically relevant model of VZV-induced pain in which prolonged hyperalgesia and allodynia occur following injection of human VZV into the rat hindpaw. The overlying hypothesis of this proposal is that by using this new rat model we will be able to better comprehend how VZV interacts with the primary afferent system to induce pain and test novel gene therapy approaches to treat VZV induced pain.
In Specific Aim 1, we will examine the biology of VZV infection in the rat by characterizing viral and pain marker protein expression in the dorsal root ganglion (DRG) sensory neurons before, during and after VZV-induced nociception, using a comprehensive panel of antibodies. We will determine which VZV proteins are expressed in the DRG at each stage and address if viral gene expression patterns correlate with the pain response and recovery from it. We will also identify types of neurons expressing VZV antigens and determine if they display an upregulation of markers of neuropathic and/or inflammatory pain at both the DRG and the spinal cord. This work will establish the underlying VZV biology in the model and whether the pain response is a result of an infectious process with similarities to human VZV lytic infections or to VZV latency.
In Specific aim 2, we will ask what specific VZV proteins are necessary to induce pain by testing the ability of: 1) various mutant VZV recombinants, each altered in a specific regulatory viral gene, and 2) various HSV vectors, each constructed to express a single VZV regulatory gene, to induce nociception. This may identify specific VZV proteins for further targeting in developing anti-pain strategies, and may lead to improved vaccines without the ability to induce PHN. The third specific aim will explore new avenues of treatment by testing the hypothesis that HSV vector-mediated delivery of modulators of pain can reduce the allodyna and hyperalgesia induced by VZV. We will investigate the use of HSV vectors expressing pro-enkephalin, GAD, the glycine receptor, and anti inflammatory proteins to treat VZV-induced hypersensitivity in the model, all of which have been shown to reduce pain in other systems. Together, exploration of this model may lead to an understanding of cellular changes that may underlie the generation of pain by VZV that will not only add to knowledge of pathogen:host interactions in VZV infection, but may help in developing new molecular targets for therapeutic intervention. This project studies a new model of pain induced by the herpesvirus varicella zoster virus that is reflective of a common and highly debilitating human disease of the elderly, post herpetic neuralgia (PHN). The examination of the model may identify new targets for the development of anti-pain strategies, and may lead to the identification of improved vaccine candidates that are unable to induce pain. The project may also identify new methods to alleviate PHN using gene therapy approaches.
|Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2018) Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]. Neuroscience 381:161|
|Kramer, Phillip; Rao, Mahesh; Stinson, Crystal et al. (2018) Aromatase Derived Estradiol Within the Thalamus Modulates Pain Induced by Varicella Zoster Virus. Front Integr Neurosci 12:46|
|Tanaka, Miyuki; Tashiro, Haruko; Omer, Bilal et al. (2017) Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells. Clin Cancer Res 23:3499-3509|
|Kramer, Phillip R; Stinson, Crystal; Umorin, Mikhail et al. (2017) Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus. Neuroscience 356:207-216|
|Kramer, Phillip R; Strand, Jennifer; Stinson, Crystal et al. (2017) Role for the Ventral Posterior Medial/Posterior Lateral Thalamus and Anterior Cingulate Cortex in Affective/Motivation Pain Induced by Varicella Zoster Virus. Front Integr Neurosci 11:27|
|Stinson, Crystal; Deng, Mohong; Yee, Michael B et al. (2017) Sex differences underlying orofacial varicella zoster associated pain in rats. BMC Neurol 17:95|
|Guedon, Jean-Marc G; Yee, Michael B; Zhang, Mingdi et al. (2015) Neuronal changes induced by Varicella Zoster Virus in a rat model of postherpetic neuralgia. Virology 482:167-80|
|Bayer, Avraham; Delorme-Axford, Elizabeth; Sleigher, Christie et al. (2015) Human trophoblasts confer resistance to viruses implicated in perinatal infection. Am J Obstet Gynecol 212:71.e1-71.e8|
|Markus, Amos; Waldman Ben-Asher, Hiba; Kinchington, Paul R et al. (2014) Cellular transcriptome analysis reveals differential expression of pro- and antiapoptosis genes by varicella-zoster virus-infected neurons and fibroblasts. J Virol 88:7674-7|
|Depledge, Daniel P; Kundu, Samit; Jensen, Nancy J et al. (2014) Deep sequencing of viral genomes provides insight into the evolution and pathogenesis of varicella zoster virus and its vaccine in humans. Mol Biol Evol 31:397-409|
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