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Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection

Genes & Immunity volume 20, pages 214–223 (2019)Cite this article

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Abstract

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.

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Acknowledgements

We wish to thank all patients involved in this study. THM was funded by The Independent Research Fund Denmark (4004-00047B) and Aarhus University Research Fund (AUFF-E-2015-FLS-66). SRP was supported by grants from The Independent Research Fund Denmark (#12-124330), The Lundbeck Foundation (R198-2015-171), and The NOVO Nordisk Foundation (NNF15OC0017462). The Ph.D. scholarship to MCT was funded by the European Union under the Horizon 2020 research and innovation program (H2020) and Marie Skłodowska-Curie Actions–Innovative Training Networks Programme MSCA-ITN GA 675278 EDGE (Training Network providing cutting-EDGE knowlEDGE on Herpes Virology and Immunology). AFH received funding from the Faculty of Health, Aarhus University.

Author contributions

THM conceived the project. AFH identified and included patients, AFH and MCT performed experiments, AFH, MCT, SRP, and THM interpreted data, MC and AFH analyzed and interpreted WES data, THM drafted the first manuscript, all authors read and approved the final version of the manuscript.

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    Authors and Affiliations

    1. Department of Infectious Diseases, Aarhus University Hospital (AUH), Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark

      Madalina E. Carter-Timofte, Anders F. Hansen & Trine H. Mogensen

    2. Department of Clinical Immunology, AUH, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark

      Mette Christiansen

    3. Department of Biomedicine AU, Wilhelm Meyers Alle 4, Aarhus C, 8000, Denmark

      Søren R. Paludan & Trine H. Mogensen

    4. Department of Clinical Medicine, Palle Juul Jensens Boulevard 82, Aarhus N, 8200, Denmark

      Trine H. Mogensen

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    1. Madalina E. Carter-Timofte
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    Correspondence to Trine H. Mogensen.

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    These authors contributed equally: Madalina E. Carter-Timofte, Anders F. Hansen.

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    Carter-Timofte, M.E., Hansen, A.F., Christiansen, M. et al. Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection. Genes Immun 20, 214–223 (2019). https://doi.org/10.1038/s41435-018-0027-y

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