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J Clin Invest. 2017 Sep 1;127(9):3543-3556. doi: 10.1172/JCI92280. Epub 2017 Aug 7.

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

Author information

1
Centre for Health Economics Research & Modeling Infectious Diseases, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
2
Department of Pediatrics, Antwerp University Hospital, Antwerp, Belgium.
3
Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium.
4
Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
5
Antwerp Unit for Data Analysis and Computation in Immunology & Sequencing, Antwerp, Belgium.
6
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
7
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.
8
Paris Descartes University, Imagine Institute, Paris, France.
9
Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
10
Department of Biomedicine and.
11
Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark.
12
Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
13
Department of Child Neurology, Queen Paola Child Hospital, Antwerp, Belgium.
14
Department of Pediatrics, Sint-Vincentius Hospital, Antwerp, Belgium.
15
Department of Pediatrics, Sint-Augustinus Hospital, Antwerp, Belgium.
16
Child Neurology, Heilig Hart Hospital Lier, Lier, Belgium.
17
Department of Development and Regeneration - Section Paediatric Neurology, University Hospitals KULeuven, Leuven, Belgium.
18
Department of Paediatric Neurology, Ghent University Hospital, Ghent, Belgium.
19
Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium.
20
Department of Public Health, Vrije Universiteit Brussel, Brussels, Belgium.
21
Department of Neurology, Pediatric Neurology, Antwerp University Hospital & University of Antwerp, Antwerp, Belgium.
22
CHU Toulouse - Children's Hospital, Pediatric Onco-Hematology, Toulouse, France.
23
Neuropediatric Department, Hospital for Children and Adolescents, gGmbH Klinikum Leverkusen, Leverkusen, Germany.
24
Department of Pediatric Pulmonology and Immunology, Charité Berlin - Campus Rudolf Virchow, Berlin, Germany.
25
FMH Pediatric Neurology, Children's Hospital, Geneva, Switzerland.
26
CHU Saint-Étienne, French Centre for Paediatric Stroke, Saint-Étienne, France.
27
Unversité Bordeaux, INSERM U1212 CNRS 5320, Bordeaux, France.
28
Howard Hughes Medical Institute, New York, New York, USA.
29
Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France.

Abstract

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.

PMID:
28783042
PMCID:
PMC5669568
DOI:
10.1172/JCI92280
[Indexed for MEDLINE]
Free PMC Article

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