3 years ago

Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration

Verónica Durán, Ulrich Kalinke, Abel Viejo-Borbolla, Kai A. Kropp, Anne Binz, Georges M. G. M. Verjans, Olav Larsen, Werner J. D. Ouwendijk, Thomas F. Schulz, Birgit Ritter, Mette M. Rosenkilde, Carina Jürgens, Thomas Krey, Tihana Lenac Rovis, Rudolf Bauerfeind, Víctor González-Motos, Beate Sodeik, Stipan Jonjic, Amanda E. I. Proudfoot, Benedikt B. Kaufer

by Víctor González-Motos, Carina Jürgens, Birgit Ritter, Kai A. Kropp, Verónica Durán, Olav Larsen, Anne Binz, Werner J. D. Ouwendijk, Tihana Lenac Rovis, Stipan Jonjic, Georges M. G. M. Verjans, Beate Sodeik, Thomas Krey, Rudolf Bauerfeind, Thomas F. Schulz, Benedikt B. Kaufer, Ulrich Kalinke, Amanda E. I. Proudfoot, Mette M. Rosenkilde, Abel Viejo-Borbolla

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.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006346

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