Manipulation of the Innate Immune Response by Varicella Zoster Virus

Abstract

Varicella zoster virus (VZV) is the causative agent of chickenpox (varicella) and shingles (herpes zoster). VZV and other members of the herpesvirus family are distinguished by their ability to establish a latent infection, with the potential to reactivate and spread virus to other susceptible individuals. This lifelong relationship continually subjects VZV to the host immune system and as such VZV has evolved a plethora of strategies to evade and manipulate the immune response. This review will focus on our current understanding of the innate anti-viral control mechanisms faced by VZV. We will also discuss the diverse array of strategies employed by VZV to regulate these innate immune responses and highlight new knowledge on the interactions between VZV and human innate immune cells.

Keywords: herpes zoster (HZ); immune evasion; innate immune response; varicella (chickenpox); varicella–zoster virus.

Figure 1

Key sites of infection during varicella zoster virus pathogenesis. Initial infection is usually mediated by inhalation of highly infectious particles from patients undergoing acute varicella infection. It is proposed that VZV initiates infections in the upper respiratory tract, infecting the epithelial mucosa. Local dendritic cells (DCs) become infected and virus is transferred to the lymph nodes (and tonsils) where T cells are infected. Viremia leads to VZV dissemination to the skin and sensory neurons of the dorsal root ganglia (DRG) where the virus establishes a latent infection. Later in life VZV has the potential to reactivate and travel via anterograde spread to the skin, resulting in productive infection and the characteristic herpes zoster rash.

Figure 2

VZV modulation of apoptosis during productive infection and the establishment of latency. During productive infection VZV infects skin cells (A) such as keratinocytes, fibroblasts, and epithelial cells. VZV induces apoptosis in skin cell types, despite the production of anti-apoptotic gene products such as VZV ORF12 and ORF63, which may act to delay apoptosis to ensure efficient viral replication and spread. (B) T cells are also infected during primary infection and act as a conduit to transport VZV to the skin and dorsal root ganglia (DRG). VZV induces apoptosis in T cells as well as other immune cells. VZV ORF66 may act to delay T cell apoptosis to promote viral dissemination. VZV establishes life-long latency in sensory neurons of the DRG (C). VZV ORF63 is able to inhibit apoptosis in these neurons which may aid in the establishment and maintenance of latency.

Figure 3

VZV interactions with human dendritic cell subsets and monocytes Immature dendritic cells (DC) are distinguishable from mature DC via differing expression levels of surface markers such as MHC II, CD80, CD83, CD86, CD54, and CD40 (A). VZV has been shown to productively infect human immature and mature monocyte derived dendritic cells and selectively regulate expression of key cell-surface molecules such as CD80, CD83, and CD86 in virus infected cells (B). VZV can also productively infect human Langerhans cells (LCs) an plasmacytoid dendritic cells (pDCs) in the skin (C). VZV infection of pDCs in vitro results in the inhibition of IFNα production. VZV also productively infects human monocytes and macrophages in culture.

Figure 4

VZV interactions with human Natural Killer cells. VZV has been shown to selectively regulate expression of NKG2D ligands, such as MICA, ULBP2, and ULBP3 in virus infected cells. VZV can also productively infect human NK cells and directly interfere with NK cell function by inhibiting the cytolytic response and modulating IFNγ and TNF cytokine production. Additionally, VZV infection can selectively modulate receptor expression on NK cells.