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Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-08-07 , DOI: 10.1172/jci92280
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

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.

中文翻译:

RNA聚合酶III的先天性错误是严重的水痘带状疱疹病毒感染的基础

水痘带状疱疹病毒(VZV)通常在初次感染时引起水痘。在极少数情况下,VZV可能在其他健康人群中引发威胁生命的疾病,但其免疫学基础仍无法解释。我们报道了4例严重的VZV急性感染,影响了无关的,否则健康的儿童,这些儿童在POLR3A(一名患者),POLR3C(一名患者)或两者(两名患者)中因罕见的错义突变而杂合为杂种POLR3APOLR3C编码RNA聚合酶III的亚基。测试的所有4名患者的白细胞均对合成或VZV衍生的DNA表现出较弱的IFN诱导作用。而且,来自3名患者的白细胞在VZV感染后显示出缺陷的IFN产生,并且降低了对VZV复制的控制。通过与相关的WT等位基因进行转导来挽救这些表型。这项工作表明,单基因或双基因的POLR3A和POLR3C缺陷使原本健康的儿童对严重VZV疾病的敏感性增加,为DNA传感器在人类免疫中的重要作用提供了证据。
更新日期:2017-09-08
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