Abstract
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.
Highlights
Varicella zoster virus (VZV) is a human alphaherpesvirus with worldwide prevalence
One of the first immune cells to respond to viral infection are natural killer (NK) cells, yet little is known about how VZV interacts with NK cells
Varicella zoster virus infection of human natural killer cells demonstrate for the first time that VZV infects human blood NK cells and can use them to pass on infection to other cells in culture
Summary
VZV is responsible for varicella during primary infection and herpes zoster following reactivation from latency in sensory ganglia. Subsequent viremia and dissemination of virus to internal organs and the skin during the prolonged incubation period (typically 14– 16 days) is considered to be facilitated by the trafficking of infected T cells [6]. This model of pathogenesis is supported by clinical studies of non-immunocompromised patients with varicella, where VZV could be cultured from peripheral blood mononuclear cells (PBMCs) isolated during the incubation phase of disease and peaking before the onset of vesicular rash [7, 8]. The delayed development of the NK cell field [14] in comparison to our understanding of T cell and B cell immunology most likely accounts for these earlier reports overlooking a possible role for NK cells
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