Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration

Abstract

Varicella zoster virus (VZV) is a highly prevalent human pathogen that establishes latency in neurons of the peripheral nervous system. Primary infection causes varicella whereas reactivation results in zoster, which is often followed by chronic pain in adults. Following infection of epithelial cells in the respiratory tract, VZV spreads within the host by hijacking leukocytes, including T cells, in the tonsils and other regional lymph nodes, and modifying their activity. In spite of its importance in pathogenesis, the mechanism of dissemination remains poorly understood. Here we addressed the influence of VZV on leukocyte migration and found that the purified recombinant soluble ectodomain of VZV glycoprotein C (rSgC) binds chemokines with high affinity. Functional experiments show that VZV rSgC potentiates chemokine activity, enhancing the migration of monocyte and T cell lines and, most importantly, human tonsillar leukocytes at low chemokine concentrations. Binding and potentiation of chemokine activity occurs through the C-terminal part of gC ectodomain, containing predicted immunoglobulin-like domains. The mechanism of action of VZV rSgC requires interaction with the chemokine and signalling through the chemokine receptor. Finally, we show that VZV viral particles enhance chemokine-dependent T cell migration and that gC is partially required for this activity. We propose that VZV gC activity facilitates the recruitment and subsequent infection of leukocytes and thereby enhances VZV systemic dissemination in humans.

Chemokine Subversion by Human Herpesviruses

“…An orthologue of HSV gG is missing in VZV. Instead, VZV expresses an envelope glycoprotein named gC that has been recently characterized as a vCKBP able to bind 27 different chemokines with nanomolar affinity (Figure 1) [11]. Like HSV gG, gC boosts the chemotactic activity of its ligands; however, its role in VZV pathogenesis is not yet defined.…”

“…It has been reported that a gC deletion mutant of VZV has reduced capacity to reach the dermis from the epidermis [12]. Since the activity of some GPCRs is known to loosen epithelial tight junctions [13], it was proposed that gC may facilitate viral dissemination across the epidermis [11].…”

How Human Herpesviruses Subvert Dendritic Cell Biology and Function

“…Interestingly, and in contrast to the observations for HSV-infected mDCs, VZV, another member among α-Herpesvirinae, does not interfere with mDC migration, but hijacks mDCs to successfully disseminate inside the host and to hide from immune recognition. By using mDCs as trojan horses, VZV facilitates its access into lymphoid organs for subsequent infection of T lymphocytes, which are strongly modulated and finally used as ferries for further viral spread, which ultimately facilitates the establishment of latency [70,176,[205][206][207].…”

Chemokines encoded by herpesviruses

“…Instead, alphaherpesviruses appear to rely on viral chemokine-binding proteins, not conserved in beta-or gammaherpesviruses, to hijack the host chemokine network. In particular, gG in HSV-1 and HSV-2, and gC in VZV bind multiple chemokines with high affinity enhancing their chemotactic activity [201,202], which differs strikingly from the typical inhibitory effect of gG orthologs in nonhuman alphaherpesviruses and of poxvirusencoded, chemokine-binding proteins [203][204][205]. Therefore, probably as a result of their distinct pathogenic mechanisms, lymphotropic and neurotropic HHVs have opted for different strategies to subvert or repurpose the host chemokine network.…”