Department of Pediatrics; Stanford University School of Medicine, Stanford, California, USA
Department of Pediatrics; Stanford University School of Medicine, Stanford, California, USA.
J Virol. 2018 May 14;92(11). doi: 10.1128/JVI.00002-18. Print 2018 Jun 1.
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 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 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 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 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 .
水痘-带状疱疹病毒（VZV）是一种嗜皮肤的人类α疱疹病毒，可引起水痘-带状疱疹和带状疱疹。水痘-带状疱疹和带状疱疹的皮肤损伤具有相似的形态，但带状疱疹在老年人中不成比例地发生，并且通常与更广泛的局部皮疹和严重的带状疱疹相关神经痛相关。我们假设皮肤衰老也会影响 VZV 向皮肤的顺行轴突运输的结果。我们利用在免疫缺陷（SCID）小鼠中维持的人皮肤异种移植物来研究在胎儿和成人皮肤异种移植物中 VZV 引起的皮肤病理学。在这里，我们发现与临床观察结果一致，与年轻人相比，老年人皮肤中的 VZV 复制增强。除了 VZV 感染的测量外，我们还检查了成人皮肤中 I 型干扰素（IFN）途径成分的表达，并研究了皮肤对 VZV 感染的增殖和炎症反应的元素。我们的结果表明，VZV 感染成人皮肤会引发内在 IFN 介导的反应，例如我们在 VZV 感染的胎儿皮肤异种移植物中所描述的反应，包括 MxA 以及早幼粒细胞白血病蛋白（PML），在病变周围的皮肤细胞中。此外，我们观察到 VZV 引起了与伤口愈合有关的改变的细胞信号传导和增殖以及炎症反应，这些反应由滤泡干细胞驱动。这些细胞变化与 VZV 诱导的 STAT3 激活一致，并表明 VZV 利用伤口愈合过程来确保将病毒有效递送至角质形成细胞。成人皮肤异种移植物提供了一种方法来进一步研究 VZV 引起的皮肤病理学。水痘-带状疱疹病毒（VZV）是引起水痘-带状疱疹和带状疱疹的病原体。带状疱疹在老年人中不成比例地发生，并且通常与更广泛的局部皮疹和严重的带状疱疹相关神经痛相关。为了研究皮肤衰老对 VZV 皮肤病变的影响，我们利用在免疫缺陷（SCID）小鼠中维持的胎儿和成人人类皮肤异种移植物。我们测量了 VZV 诱导的皮肤病理学，检查了成人皮肤中 I 型干扰素（IFN）途径成分的表达，并研究了皮肤对 VZV 感染的增殖和炎症反应的元素。我们的结果表明，异种移植物中保留了衰老皮肤的特征；与临床观察结果一致，与年轻人相比，老年人皮肤中的 VZV 复制增强；并且 VZV 感染引发了改变的细胞信号传导和炎症反应。成人皮肤异种移植物提供了一种方法来进一步研究 VZV 引起的皮肤病理学。
