Jacob Giehm Mikkelsen

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Benson Ogunjimi, Antwerp Unit for Data Analysis and Computation in Immunology & Sequencing, Antwerp, Belgium.
  • ,
  • Shen-Ying Zhang, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Katrine Biehl Sørensen, Institut for Klinisk Medicin - Infektionssygdomme
  • ,
  • Kristian A Skipper
  • Madalina Carter-Timofte
  • Gaspard Kerner, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Stefanie Luecke, Department of Biomedicine, Aarhus University, Aarhus, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark. Electronic address: srp@biomed.au.dk.
  • ,
  • Thaneas Prabakaran
  • Yujia Cai, Department of Biomedicine, Aarhus University, Aarhus, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark. Electronic address: srp@biomed.au.dk.
  • ,
  • Josephina Meester, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Esther Bartholomeus, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Nikhita Ajit Bolar, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Geert Vandeweyer, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Charlotte Claes, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Yasmine Sillis, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Lazaro Lorenzo, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Raffaele A Fiorenza, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Soraya Boucherit, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Charlotte Dielman, Department of Child Neurology, Queen Paola Child Hospital, Antwerp, Belgium.
  • ,
  • Steven Heynderickx, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp University Hospital, Edegem, Belgium.
  • ,
  • George Elias, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp University Hospital, Edegem, Belgium.
  • ,
  • Andrea Kurotova, Department of Pediatrics, Sint-Vincentius Hospital, Antwerp, Belgium.
  • ,
  • Ann Vander Auwera, Department of Pediatrics, Sint-Augustinus Hospital, Antwerp, Belgium.
  • ,
  • Lieve Verstraete, Child Neurology, Heilig Hart Hospital Lier, Lier, Belgium.
  • ,
  • Lieven Lagae, Department of Development and Regeneration - Section Paediatric Neurology, University Hospitals KULeuven, Leuven, Belgium.
  • ,
  • Helene Verhelst, Department of Paediatric Neurology, Ghent University Hospital, Ghent, Belgium.
  • ,
  • Anna Jansen, Department of Public Health, Vrije Universiteit Brussel, Brussels, Belgium.
  • ,
  • Jose Ramet, Department of Pediatrics, Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Arvid Suls, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Evelien Smits, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp University Hospital, Edegem, Belgium.
  • ,
  • Berten Ceulemans, Department of Neurology, Pediatric Neurology, Antwerp University Hospital & University of Antwerp, Antwerp, Belgium.
  • ,
  • Lut Van Laer, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Genevieve Plat Wilson, CHU Toulouse - Children's Hospital, Pediatric Onco-Hematology, Toulouse, France.
  • ,
  • Jonas Kreth, Neuropediatric Department, Hospital for Children and Adolescents, gGmbH Klinikum Leverkusen, Leverkusen, Germany.
  • ,
  • Capucine Picard, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Horst Von Bernuth, Department of Pediatric Pulmonology and Immunology, Charité Berlin - Campus Rudolf Virchow, Berlin, Germany.
  • ,
  • Joël Fluss, FMH Pediatric Neurology, Children's Hospital, Geneva, Switzerland.
  • ,
  • Stephane Chabrier, CHU Saint-Étienne, French Centre for Paediatric Stroke, Saint-Étienne, France.
  • ,
  • Laurent Abel, Department of Paediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris-Descartes University, Paris, France.
  • ,
  • Geert Mortier, Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
  • ,
  • Sebastien Fribourg, Unversité Bordeaux, INSERM U1212 CNRS 5320, Bordeaux, France.
  • ,
  • Jacob Giehm Mikkelsen
  • Jean-Laurent Casanova, Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France.
  • ,
  • Søren R Paludan
  • Trine H Mogensen

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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
ISSN0021-9738
DOI
StatusUdgivet - 1 sep. 2017

Se relationer på Aarhus Universitet Citationsformater

ID: 116292603