Varicella zoster virus productively infects human natural killer cells and manipulates phenotype

• Published in: PLoS pathogens 2018-04, Vol.14 (4), p.e1006999-e1006999
• Main Authors: Campbell, Tessa Mollie, McSharry, Brian Patrick, Steain, Megan, Ashhurst, Thomas Myles, Slobedman, Barry, Abendroth, Allison
• Format: Article
• Language: English
• Subjects: Activation; Analysis; Biology and life sciences; CD16 antigen; CD57 antigen; Cell culture; Cell surface; Chemokine receptors; Chicken pox; Cytokines; Data processing; Discipline; Epithelial cells; Fc receptors; Flow cytometry; Funding; Gene expression; Genotype & phenotype; Health aspects; Herpes zoster; Human behavior; Immune response; Immune system; Immunoglobulin G; Immunology; Infections; Infectious diseases; Killer cells; Kinases; Latency; Lesions; Lymphocytes; Medicin och hälsovetenskap; Medicine and health sciences; Natural killer cells; Pathogenesis; Peripheral blood; Phenotypes; Protein transport; Receptors; Research and Analysis Methods; Skin; Supervision; T cell receptors; Varicella; Varicella-zoster virus; Viral infections; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006999

Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, responsible for varicella upon primary infection and herpes zoster following reactivation from latency. To establish lifelong infection, VZV employs strategies to evade and manipulate the immune system to its advantage in disseminating virus. As innate lymphocytes, natural killer (NK) cells are part of the early immune response to infection, and have been implicated in controlling VZV infection in patients. Understanding of how VZV directly interacts with NK cells, however, has not been investigated in detail. In this study, we provide the first evidence that VZV is capable of infecting human NK cells from peripheral blood in vitro. VZV infection of NK cells is productive, supporting the full kinetic cascade of viral gene expression and producing new infectious virus which was transmitted to epithelial cells in culture. We determined by flow cytometry that NK cell infection with VZV was not only preferential for the mature CD56dim NK cell subset, but also drove acquisition of the terminally-differentiated maturity marker CD57. Interpretation of high dimensional flow cytometry data with tSNE analysis revealed that culture of NK cells with VZV also induced a potent loss of expression of the low-affinity IgG Fc receptor CD16 on the cell surface. Notably, VZV infection of NK cells upregulated surface expression of chemokine receptors associated with trafficking to the skin -a crucial site in VZV disease where highly infectious lesions develop. We demonstrate that VZV actively manipulates the NK cell phenotype through productive infection, and propose a potential role for NK cells in VZV pathogenesis.