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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.

SUBMITTER: Ogunjimi B

PROVIDER: S-EPMC5669568 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

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

The Journal of clinical investigation 20170807 9

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 P ...[more]

PMID: 28783042

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Project description:BackgroundPneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP).MethodsThis was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015.ResultsOne hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU-acquired infections.ConclusionsSevere VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection.

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

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

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