RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections

In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity. Here we describe the roles of POL III in housekeeping and immune surveillance during VZV infection. We present the latest knowledge on the role of POL III in VZV infection and discuss outstanding questions related to the role of POL III in VZV immunity, and how this insight can be translated into clinical medicine. Accumulation of DNA in the cytoplasm is detected by sensor proteins to induce antimicrobial defences, including antiviral cytokines called interferons. Heterozygous mutations in the cytosolic DNA sensor RNA POL III are associated with elevated risk of developing severe disease during VZV infection. Nuclear POL III transcribes 5S RNA, while cytoplasmic POL III transcribes AT-rich DNA into an RNA form that activates the immune receptor RIG-I. Heterozygous mutations in POL III impair immune sensing, but retain nuclear transcription. Immune control of VZV infection involves a number of immune receptors, including POL III, which work in a cell-type-dependent manner to orchestrate antiviral defences. The development of whole-exome/genome sequencing techniques has led to identification of novel primary immunodeficiencies with increased susceptibility to a narrow set of infections.