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

J Virol. 2018 May 14;92(11):e00002-18. doi: 10.1128/JVI.00002-18. Print 2018 Jun 1.

Abstract

Varicella-zoster virus (VZV) is the skin-tropic human alphaherpesvirus responsible for both varicella-zoster and herpes zoster. Varicella-zoster and herpes zoster skin lesions have similar morphologies, but herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. We hypothesized that skin aging could also influence the outcome of the anterograde axonal transport of VZV to skin. We utilized human skin xenografts maintained in immunodeficient (SCID) mice to study VZV-induced skin pathology in vivo in fetal and adult skin xenografts. Here we found that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations. In addition to measures of VZV infection, we examined the expression of type I interferon (IFN) pathway components in adult skin and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo Our results demonstrated that VZV infection of adult skin triggers intrinsic IFN-mediated responses such as we have described in VZV-infected fetal skin xenografts, including MxA as well as promyelocytic leukemia protein (PML), in skin cells surrounding lesions. Further, we observed that VZV elicited altered cell signaling and proliferative and inflammatory responses that are involved in wound healing, driven by follicular stem cells. These cellular changes are consistent with VZV-induced activation of STAT3 and suggest that VZV exploits the wound healing process to ensure efficient delivery of the virus to keratinocytes. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivoIMPORTANCE Varicella-zoster virus (VZV) is the agent responsible for both varicella-zoster and herpes zoster. Herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. To examine the effect of skin aging on VZV skin lesions, we utilized fetal and adult human skin xenografts maintained in immunodeficient (SCID) mice. We measured VZV-induced skin pathology, examined the expression of type I interferon (IFN) pathway components in adult skin, and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo Our results demonstrate that characteristics of aging skin are preserved in xenografts; that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations; and that VZV infection elicits altered cell signaling and inflammatory responses. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivo.

Keywords: STAT3; interferons; skin; transmission; varicella-zoster virus; viral pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aging / pathology*
  • Animals
  • Disease Models, Animal
  • Enzyme Activation
  • Herpesvirus 3, Human / growth & development*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Promyelocytic Leukemia Protein / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Skin / virology
  • Skin Diseases / pathology
  • Skin Diseases / virology
  • Skin Transplantation
  • Transplantation, Heterologous
  • Varicella Zoster Virus Infection / pathology*
  • Varicella Zoster Virus Infection / virology
  • Virus Replication / physiology*
  • Wound Healing / physiology

Substances

  • Promyelocytic Leukemia Protein
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • PML protein, human