Infection and Functional Modulation of Human Monocytes and Macrophages by Varicella-Zoster Virus

Abstract

Varicella-zoster virus (VZV) is associated with viremia during primary infection that is presumed to stem from infection of circulating immune cells. While VZV has been shown to be capable of infecting a number of different subsets of circulating immune cells, such as T cells, dendritic cells, and NK cells, less is known about the interaction between VZV and monocytes. Here, we demonstrate that blood-derived human monocytes are permissive to VZV replication in vitro. VZV-infected monocytes exhibited each temporal class of VZV gene expression, as evidenced by immunofluorescent staining. VZV virions were observed on the cell surface and viral nucleocapsids were observed in the nucleus of VZV-infected monocytes by scanning electron microscopy. In addition, VZV-infected monocytes were able to transfer infectious virus to human fibroblasts. Infected monocytes displayed impaired dextran-mediated endocytosis, and cell surface immunophenotyping revealed the downregulation of CD14, HLA-DR, CD11b, and the macrophage colony-stimulating factor (M-CSF) receptor. Analysis of the impact of VZV infection on M-CSF-stimulated monocyte-to-macrophage differentiation demonstrated the loss of cell viability, indicating that VZV-infected monocytes were unable to differentiate into viable macrophages. In contrast, macrophages differentiated from monocytes prior to exposure to VZV were highly permissive to infection. This study defines the permissiveness of these myeloid cell types to productive VZV infection and identifies the functional impairment of VZV-infected monocytes. IMPORTANCE Primary VZV infection results in the widespread dissemination of the virus throughout the host. Viral transportation is known to be directly influenced by susceptible immune cells in the circulation. Moreover, infection of immune cells by VZV results in attenuation of the antiviral mechanisms used to control infection and limit spread. Here, we provide evidence that human monocytes, which are highly abundant in the circulation, are permissive to productive VZV infection. Furthermore, monocyte-derived macrophages were also highly permissive to VZV infection, although VZV-infected monocytes were unable to differentiate into macrophages. Exploring the relationships between VZV and permissive immune cells, such as human monocytes and macrophages, elucidates novel immune evasion strategies and provides further insight into the control that VZV has over the immune system.

Manipulation of the Innate Immune Response by Varicella Zoster Virus

“…This work was corroborated by a report demonstrating VZV infection of monocytes, NKT cells and B lymphocytes (150) and by productive infection of a THP-1 monocytic cell line (89). Although evidence suggesting monocyte differentiation to macrophage may be influenced by VZV infection in vivo, macrophage infection in vitro has previously been observed (56,148). As such, it is likely that although monocytes and macrophages represent a dynamic axis for the induction and maintenance of anti-viral states, VZV is able to counteract this effective branch of the innate immune system through direct infection and immune evasion strategies.…”

“…More recently however, our laboratory performed an investigation into the susceptibility of human monocytes and macrophages to VZV infection. We reported productive VZV infection of both freshly isolated human monocytes and differentiated macrophages (56). Interestingly, macrophages were highly permissive to VZV infection.…”

“…VZV has also been shown to induce apoptosis in immune cells such as T cells, B cells, and monocytes (54)(55)(56), however the factors which cause this induction are unclear. Investigating whether the downregulation of Bcl-2 occurs in VZV induced apoptosis in human immune cell types would be pertinent to determine whether VZV apoptosis induction occurs through a similar pathway in all cell types.…”

Polyinosinic‐polycytidylic acid induces innate immune responses via Toll‐like receptor 3 in human ovarian granulosa cells

“…CD14 + monocytes were derived from healthy human blood as described previously . Briefly, peripheral blood mononuclear cells from healthy volunteers at China‐Japan Friendship Hospital were isolated by gradient centrifugation with Ficoll‐Paque (GE Healthcare Bio‐Science).…”

The beneficial effects of varicella zoster virus

“…Mononuclear cells: Infection of the immune cells by VZV results in attenuation of the antiviral mechanisms to control the infection and limit spread of the virus [320]. Several studies have shown that VZV productively infects human peripheral blood mononuclear cells (PBMNCs) and the infected PBMNCs then disseminate the virus to distal organs to produce clinical disease [320][321][322][323][324]. VZV induces an IFNmediated Th1 reaction in PBMNCs.…”