STING Is Involved in Antiviral Immune Response against VZV Infection via the Induction of Type I and III IFN Pathways

Abstract

Varicella zoster virus (VZV) is a human-restricted α-herpesvirus that exhibits tropism for the skin. The VZV host receptors and downstream signaling pathways responsible for the antiviral innate immune response in the skin are not completely understood. Here, we show that STING mediates an important host defense against VZV infection in dermal cells including human dermal fibroblasts and HaCaT keratinocytes. Inhibition of STING using small interfering-RNA or short hairpin RNA-mediated gene disruption resulted in enhanced viral replication but diminished IRF3 phosphorylation and induction of IFNs and proinflammatory cytokines. Pretreatment with STING agonists resulted in reduced VZV glycoprotein E expression and viral replication. Additionally, using RNA sequencing to analyze dual host and VZV transcriptomes, we identified several host immune genes significantly induced by VZV infection. Furthermore, significant up-regulation of IFN-λ secretion was observed after VZV infection, partly through a STING-dependent pathway; IFN-λ was shown to be crucial for antiviral defense against VZV in human dermal cells. In conclusion, our data provide an important insight into STING-mediated induction of type I and III IFNs and subsequent antiviral signaling pathways that regulate VZV replication in human dermal cells.

Manipulation of the Innate Immune Response by Varicella Zoster Virus

“…Knockdown of RIG-1 in the context of VZV infection does not affect viral titers in MRC-5 cells, however in human dermal fibroblasts (HDF) RIG-1 overexpression caused a significant suppression of viral replication (86). This suggests that in HDF a RIG-1 induced IFN response may play a role in controlling VZV infection, however RIG-1 is not essential for the control of VZV replication (86). As of yet there have been no VZV ORFs implicated in the inhibition of RIG-1 sensing, however VZV ORFs do target downstream transcription factors such as NFκB, that are involved in the production of inflammatory cytokines (87).…”

“…Retinoic acid-inducible gene I (RIG-1) is a cytoplasmic PRR which senses both RNA and DNA viruses and can result in the production of the type I IFN response (85). Knockdown of RIG-1 in the context of VZV infection does not affect viral titers in MRC-5 cells, however in human dermal fibroblasts (HDF) RIG-1 overexpression caused a significant suppression of viral replication (86). This suggests that in HDF a RIG-1 induced IFN response may play a role in controlling VZV infection, however RIG-1 is not essential for the control of VZV replication (86).…”

“…Wang and colleagues demonstrated that the ability of VZV ORF61 to bind small ubiquitin-like modifier (SUMO) is required to counterbalance PML nuclear body-mediated control of VZV replication, and enable the formation of skin lesions during varicella and herpes zoster (91). Recently it has been shown that human skin cells including dermal fibroblasts and HaCaT keratinocytes can sense cytosolic VZV DNA through stimulator of interferon genes (STING), triggering secretion of type I and III interferons, which limited VZV replication (86).…”

“…Further studies to understand the distinct activities of type I and II IFNs in regulating infection will potentially tease apart the roles played by distinct IFNs in regulating infection during different phases of the viral lifecycle. Similarly the role of type III IFNs in viral infections is becoming clear, particularly at mucosal sites, and a recent report indicated that VZV infection can promote IFNλ1/3 and IFNλ2 production in keratinocytes in a STING dependent manner and IFNλ has direct anti-viral activity in vitro (86). Additional study will be required to fully define the role of type III IFN (IFNλ) during VZV infection.…”

Kallikrein-6–Regulated Pathways Shed Light on New Potential Targets in Varicella Zoster Virus Infection

“…Initial host defenses are mediated by innate immune responses involving natural killer cells and type 1 interferons, and VZV viral replication is ultimately controlled by adaptive immune responses (Arvin et al, 1986;Gershon and Steinberg, 1979;Kim et al, 2017;Tilden et al, 1986). In particular, anti-VZV glycoprotein gE T helper type 1 immunity is essential for control of the viremic phase with contributions by IgM, IgA, and IgG antibodies that are directed against a wide range of VZV proteins (Hayward et al, 1991).…”