Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Varicella zoster virus (VZV) causes chickenpox but can rarely lead to severe, life-threatening illness in healthy individuals.
• The immunological underpinnings of severe VZV disease in immunocompetent hosts are not fully understood.

Purpose of the Study:

• To investigate the genetic and immunological basis for severe VZV infections in otherwise healthy children.
• To identify specific genetic defects that may predispose individuals to severe VZV disease.

Main Methods:

• Case study of four unrelated children with severe VZV infections (central nervous system or lung).
• Genetic analysis for mutations in POLR3A and POLR3C genes, which encode RNA polymerase III subunits.
• Immunological assays on patient leukocytes to assess interferon (IFN) induction and response to VZV infection.
• Functional rescue experiments using wild-type (WT) alleles.

Main Results:

• Four children with severe VZV infections were identified as heterozygous for rare missense mutations in POLR3A, POLR3C, or both.
• Patient leukocytes showed impaired IFN induction upon stimulation with DNA and defective IFN production and VZV replication control upon VZV infection.
• These cellular phenotypes were reversed by gene correction with WT alleles.

Conclusions:

• Monogenic or digenic deficiencies in POLR3A and POLR3C increase susceptibility to severe VZV disease in healthy children.
• This study highlights the critical role of RNA polymerase III and DNA sensing pathways in innate immunity against VZV.
• Defects in DNA sensing mechanisms represent a novel risk factor for severe VZV infections.