Varicella Zoster Virus Alters Expression of Cell Adhesion Proteins in Human Perineurial Cells via Interleukin 6.

Abstract

In temporal arteries (TAs) from patients with giant cell arteritis, varicella zoster virus (VZV) is seen in perineurial cells that surround adventitial nerve bundles and form the peripheral nerve-extrafascicular tissue barrier (perineurium). We hypothesized that during VZV reactivation from ganglia, virus travels transaxonally and disrupts the perineurium to infect surrounding cells. Mock- and VZV-infected primary human perineurial cells (HPNCs) were examined for alterations in claudin-1, E-cadherin, and N-cadherin. Conditioned supernatant was analyzed for a soluble factor(s) mediating these alterations and for the ability to increase cell migration. To corroborate in vitro findings, a VZV-infected TA was examined. In VZV-infected HPNCs, claudin-1 redistributed to the nucleus; E-cadherin was lost and N-cadherin gained, with similar changes seen in VZV-infected perineurial cells in a TA. VZV-conditioned supernatant contained increased interleukin 6 (IL-6) that induced E-cadherin loss and N-cadherin gain and increased cell migration when added to uninfected HPNCs; anti-IL-6 receptor antibody prevented these changes. IL-6 secreted from VZV-infected HPNCs facilitated changes in E- and N-cadherin expression and cell migration, reminiscent of an epithelial-to-mesenchymal cell transition, potentially contributing to loss of perineurial cell barrier integrity and viral spread. Importantly, an anti-IL-6 receptor antibody prevented virus-induced perineurial cell disruption.