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

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 5

PBMCs from P1, P3, and P4 exhibit defective ability to produce IFNs during VZV infection and to control the virus.

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PBMCs from P1, P3, and P4 exhibit defective ability to produce IFNs duri...
PBMCs from P1–P4 (A–C and F–H), 3 VZV patients not carrying POL III gene mutations (D and E), and age-matched healthy controls (A–H) were treated with VZV-infected MeWo cells. Total RNA was harvested 48 hours after initiation of coculture with VZV-MeWo cells. (F and G) PBMCs from P1–P4 and age-matched healthy controls were treated with IAV, measles virus, poliovirus, or reovirus (Reo) (all MOI 5). Total RNA was harvested 6 hours later. Levels of IFNA2, IFNL1, CXCL10, and Orf63 mRNA were determined by RT-qPCR as indicated. For all PCR data, the levels of the mRNA of interest were normalized to GAPDH, and data are presented as mean ± SD of 3 replicates from 3 independent experiments. Average of 4 age-matched controls. 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.