The Biology of Varicella-Zoster Virus Replication in the Skin

Abstract

The replication of varicella-zoster virus (VZV) in skin is critical to its pathogenesis and spread. Primary infection causes chickenpox, which is characterised by centrally distributed skin blistering lesions that are rich in infectious virus. Cell-free virus in the cutaneous blistering lesions not only spreads to cause further cases, but infects sensory nerve endings, leading to the establishment of lifelong latency in sensory and autonomic ganglia. The reactivation of virus to cause herpes zoster is again characterised by localised painful skin blistering rash containing infectious virus. The development of in vitro and in vivo models of VZV skin replication has revealed aspects of VZV replication and pathogenesis in this important target organ and improved our understanding of the vaccine strain vOKa attenuation. In this review, we outline the current knowledge on VZV interaction with host signalling pathways, the viral association with proteins associated with epidermal terminal differentiation, and how these interconnect with the VZV life cycle to facilitate viral replication and shedding.

Keywords: autophagy; cutaneous blistering lesions; epidermal differentiation; epidermis; immunity; keratinocytes; keratins; skin; vaccine; varicella-zoster virus.

Figure 1

Schematic of the human epidermis. The human epidermis is a pluristratified tissue made up of basal, spinous, granular, upper-granular and cornified layers, in ascending order. The keratinocytes in the basal layer express keratins K5 and K14, as well as K15, which are then substituted by markers of epidermal differentiation such as K1, K10, IVL in the spinous layer. With progression of differentiation, other markers such as FLG and loricrin are expressed in the granular layer. The keratinocytes at the level of the cornified layer are called corneocytes as they are devoid of organelles and nuclei and are finally sloughed off.

Figure 2

Schematic of VZV interplay with epidermal terminal differentiation. Left model of VZV-infected epidermis: VZV infects epidermal basal keratinocytes where starts to replicate. The newly formed virions in the basal keratinocytes are immature and do not express glycoproteins. In the suprabasal layers VZV virions mature together with epidermal differentiation and express glycoproteins. They also spread cell-to-cell via syncytia formation. At the uppermost epidermal layers mature and cell-free virions are released. Right panel: summary of the major changes induced by VZV to epidermal host pathways. They include in the spinous layer the downregulation of keratin K10 due to its degradation and caused by MDM2, which is upregulated by increased levels of KLK6. K10 downregulation has a structural effect on blister and syncytia formation, but also a signalling effect by upregulating NR4A1, which in turn induces activation of autophagy pathways. Keratin K15, which is normally expressed in the basal layer, is upregulated and its expression is found also in differentiated keratinocytes. K4 and K13 are also upregulated in differentiated keratinocytes during VZV infection.