Age-Associated Differences in Infection of Human Skin in the SCID Mouse Model of Varicella-Zoster Virus Pathogenesis

Zerboni, Leigh; Sung, Phillip; Lee, Gordon; Arvin, Ann M.

doi:10.1128/jvi.00002-18

Cited by 9 publications

(16 citation statements)

References 58 publications

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“…HCMV replication was poor when introduced by scarification; VZV replication was similar, and mainly found in the epidermis, when either inoculation route was used. Therefore, skin was inoculated by scarification with VZV-ORF57-Luc, a robust bacterial artificial chromosome (BAC)-derived recombinant VZV based on the POka genome that contains a luciferase reporter linked to ORF57, which places the virus near basal keratinocytes, the preferred target cell in the epidermis and hair follicles (11,15). VZV is thought to enter the skin when infected T cells extravasate from capillaries surrounding hair follicles during primary infection and from axon termini during reactivation (8).…”

Section: Resultsmentioning

confidence: 99%

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A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus

Lloyd

Smith

Tighe

et al. 2020

J Virol

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The herpesviruses varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) are endemic viruses. VZV causes varicella (chicken pox) and herpes zoster (shingles), while HCMV causes serious disease in immunocompromised patients and neonates. More effective, less toxic antivirals are needed, necessitating better models to study these viruses and evaluate antivirals. Previously, VZV and HCMV models used fetal tissue; here, we developed an adult human skin model to study VZV and HCMV in culture and in vivo. While VZV is known to grow in skin, it was unknown whether skin could support an HCMV infection. We used TB40/E HCMV and POka VZV strains to evaluate virus tropism in skin organ culture (SOC) and skin xenograft mouse models. Adult human skin from reduction mammoplasties was prepared for culture on NetWells or mouse implantation. In SOC, VZV infected the epidermis, and HCMV infected the dermis. Specifically, HCMV infected fibroblasts, endothelial and hematopoietic cells, with some infected cells able to transfer infection. VZV and HCMV mouse models were developed by subcutaneous transplantation of skin into SCID/beige or athymic nude mice at 2 independent sites. Viruses were inoculated directly into one xenograft and widespread infection was observed for VZV and HCMV. Notably, we detected VZV- and HCMV-infected cells in the contralateral, uninoculated xenografts, suggesting dissemination from infected xenografts occurred. For the first time, we showed HCMV successfully grows in adult human skin, as does VZV. Thus, this novel system may provide a much-needed pre-clinical small animal model for HCMV and VZV, and potentially other human-restricted viruses. IMPORTANCE Varicella-zoster virus and human cytomegalovirus infect a majority of the global population. While they often cause mild disease, serious illness and complications can arise. Unfortunately, there are few effective drugs to treat these viruses, and many are toxic. To complicate this, these viruses are restricted to replication in human cells and tissues, making them difficult to study in traditional animal models. Current models rely heavily on fetal tissues, can be prohibitively expensive, and are often complicated to generate. While fetal tissue models provide helpful insights, it's necessary to study human viruses in human tissue systems to fully understand these viruses and adequately evaluate novel antivirals. Adult human skin is an appropriate model for these viruses because many target cells are present, including basal keratinocytes, fibroblasts, dendritic cells, and lymphocytes. Skin models, in culture and xenografts in immunodeficient mice, have potential for research on viral pathogenesis, tissue tropism, dissemination, and therapy.

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Section: Resultsmentioning

confidence: 99%

“…In previously published reports, we used fetal skin to understand VZV growth kinetics and study the effects of antiviral drugs (11)(12)(13). Adult skin is preferable, as it is fully differentiated and constitutes the tissue environment during a VZV infection (14,15). In contrast, the use of human skin to study HCMV is novel.…”

mentioning

confidence: 99%

A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus

Lloyd

Smith

Tighe

et al. 2020

J Virol

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“…Implanted tissues retain many characteristics and structural organization for long periods in these mice, despite an unnatural ectopic location (McCune et al, 1988; Mosier et al, 1988). The application of the SCID-hu mice for VZV was pioneered by Moffat et al (1995), using skin tissue from fetuses and, more recently, adults (Zerboni et al, 2018). Immune cells from grafted human fetal thymus and liver tissue are placed beneath the mouse kidney capsule, as are fetal ganglia.…”

Section: In Vivo Models Of Vzv Latencymentioning

confidence: 99%

Modeling Varicella Zoster Virus Persistence and Reactivation – Closer to Resolving a Perplexing Persistent State

2019

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The latent state of the human herpesvirus varicella zoster virus (VZV) has remained enigmatic and controversial. While it is well substantiated that VZV persistence is established in neurons after the primary infection (varicella or chickenpox), we know little of the types of neurons harboring latent virus genomes, if all can potentially reactivate, what exactly drives the reactivation process, and the role of immunity in the control of latency. Viral gene expression during latency has been particularly difficult to resolve, although very recent advances indicate that it is more restrictive than was once thought. We do not yet understand how genes expressed in latency function in the maintenance and reactivation processes. Model systems of latency are needed to pursue these questions. This has been especially challenging for VZV because the development of in vivo models of VZV infection has proven difficult. Given that up to one third of the population will clinically reactivate VZV to develop herpes zoster (shingles) and suffer from its common long term problematic sequelae, there is still a need for both in vivo and in vitro model systems. This review will summarize the evolution of models of VZV persistence and address insights that have arisen from the establishment of new in vitro human neuron culture systems that not only harbor a latent state, but permit experimental reactivation and renewed virus production. These models will be discussed in light of the recent data gleaned from the study of VZV latency in human cadaver ganglia.

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“…8 Reactivated and subsequently replicated VZVs in neural cells exhibit anterograde axonal transport to skin. 9 HZ/PHN is dermatome restricted, even though it can be present in more than 1 dermatome. The most painful areas associated with HZ and PHN are usually the partial regions innervated by distal nerve branches instead of the entire nerve distribution area.…”

Section: Introductionmentioning

confidence: 99%

“…VZV is a neurotropic 7 and skin‐tropic virus 8 . Reactivated and subsequently replicated VZVs in neural cells exhibit anterograde axonal transport to skin 9 . HZ/PHN is dermatome restricted, even though it can be present in more than 1 dermatome.…”

Section: Introductionmentioning

confidence: 99%

Local Administration of Methylcobalamin for Subacute Ophthalmic Herpetic Neuralgia: A Randomized, Phase III Clinical Trial

et al. 2020

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Objectives: The ophthalmic branch of the trigeminal nerve is one of the most frequently involved sites of postherpetic neuralgia. A single-center randomized controlled study was conducted to evaluate the efficacy of local methylcobalamin injection for subacute ophthalmic herpetic neuralgia (SOHN). Methods: One hundred and five patients with a pain score of 4 or greater were randomized to receive a combination of methylcobalamin and lidocaine via local injection (LM group, n = 35), intramuscular methylcobalamin and local lidocaine injection (IM group, n = 35), and oral methylcobalamin tablet and lidocaine local injection (OM group, n = 35) for 4 weeks. Multilevel mixed modeling was employed to examine treatment responses. Results: Pain scores were reduced in all groups, but this reduction was significantly greater in the LM group (6.7 at baseline vs. 2.8 at endpoint) when compared with systemic administration (IM group 6.8 vs. 4.9, OM group 6.7 vs. 5.1). Clinically relevant reduction of pain (>30%) was seen in 91% of patients in the LM group, a significantly greater proportion than in the systemic groups (66% IM group, 57% OM group). Analgesic use reduced significantly in the LM group (94% at baseline vs. 6% at endpoint) but not in systemic groups (IM group 97% vs. 86%, OM group 94% vs. 80%). Health-related quality of life was higher in the LM group than in the systemic groups. In mixed modelling, increased age was associated with a lower response to methylcobalamin. Conclusions: This study indicates that local injection of methylcobalamin produces significant pain relief from SOHN and is superior to systemic administration. &

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Age-Associated Differences in Infection of Human Skin in the SCID Mouse Model of Varicella-Zoster Virus Pathogenesis

Cited by 9 publications

References 58 publications

A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus

A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus

Modeling Varicella Zoster Virus Persistence and Reactivation – Closer to Resolving a Perplexing Persistent State

Local Administration of Methylcobalamin for Subacute Ophthalmic Herpetic Neuralgia: A Randomized, Phase III Clinical Trial

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