Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencin...

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Bibliographic Details
Published in:Genes and immunity 2019-03, Vol.20 (3), p.214-223
Main Authors: Carter-Timofte, Madalina E., Hansen, Anders F., Christiansen, Mette, Paludan, Søren R., Mogensen, Trine H.
Format: Article
Language:English
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Biomedical and Life Sciences
Biomedicine
Cancer Research
Chicken pox
Chickenpox
Cytokines
Deoxyribonucleic acid
Disease susceptibility
DNA
DNA-directed RNA polymerase
EDTA
Encephalitis
Gene Expression
Gene mutation
Genes
Genetic aspects
Genomes
Genomics
Herpes viruses
Herpes zoster
Human Genetics
Immunology
Infection
Infections
Infectious diseases
Inflammation
Medical research
Mutation
Pathogenesis
Patients
Risk factors
RNA
RNA polymerase
Varicella
Varicella-zoster virus
Virus replication
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Summary:Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E . In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.
ISSN:1466-4879
1476-5470
DOI:10.1038/s41435-018-0027-y