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Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections
Benson Ogunjimi, … , Søren R. Paludan, Trine H. Mogensen
Benson Ogunjimi, … , Søren R. Paludan, Trine H. Mogensen
Published August 7, 2017
Citation Information: J Clin Invest. 2017;127(9):3543-3556. https://doi.org/10.1172/JCI92280.
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Research Article Genetics Infectious disease

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

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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.

Authors

Benson Ogunjimi, Shen-Ying Zhang, Katrine B. Sørensen, Kristian A. Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A. Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven Heynderickx, George Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joël Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Søren R. Paludan, Trine H. Mogensen

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Figure 3

AT content in herpesvirus genomes.

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AT content in herpesvirus genomes.
(A) The content and distribution of A...
(A) The content and distribution of AT-rich regions in the genomes of VZV were compared with those in the genomes of HSV-1, HSV-2, EBV, and CMV using the EMBOSS Isochore algorithm. Data are presented to show regions in the genome with AT content greater than 70% AT. The regions harboring the sequences termed “VZV-AT-high DNA” and “VZV-AT-low DNA” are indicated by blue and red stars, respectively. (B) Sequences and genome localization of “VZV-AT-high” and “VZV-AT-low” DNA. (C and D) PBMCs from P1–P4 and 3 controls were transfected with VZV-AT-high or VZV-AT-low DNA (2 μg/ml). Total RNA was harvested 6 hours later, and levels of IFNA2 mRNA were determined by RT-qPCR. Data are presented as mean ± SD of 3 replicates from 3 independent experiments. UT, untreated. NS, P > 0.05; *0.01 < P < 0.05; **0.01 < P < 0.001; ***0.001 < P < 0.0001. Groups were compared pairwise using post hoc t tests based on data from all groups and 1-way ANOVA.
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