Thomsen Michelle M, Tyrberg Tobias, Skaalum Kristoffer, Carter-Timofte Madalina, Freytag Mette R, Norberg Peter, Helleberg Marie, Storgaard Merete, Nielsen Henrik, Bodilsen Jacob, Grahn Anna, Mogensen Trine H
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
J Infect Dis. 2021 Dec 15;224(12):2122-2132. doi: 10.1093/infdis/jiab254.
Infection with varicella zoster virus (VZV) may involve different central nervous system (CNS) manifestations, including meningitis, encephalitis, and vasculitis. In cases in which otherwise healthy individuals are affected, an inborn error of immunity may underlie increased susceptibility or severity of infection.
We collected a cohort of 17 adults who experienced VZV encephalitis and performed whole exome sequencing. Patient peripheral blood mononuclear cells were infected with VZV, and innate antiviral interferon (IFN) and cytokine responses as well as viral replication were evaluated. Data were analyzed by Mann-Whitney U test.
We identified a total of 21 different potentially disease-causing variants in a total of 13 of the 17 patients included. These gene variants were within 2 major functional clusters: (1) innate viral sensors and immune pathways and (2) autophagy pathways. Antiviral IFN and cytokine responses were abnormal in the majority of patients, whereas viral replication was increased in only 2 of 17 patients.
This study identifies a list of variants of pathogenic potential, which may serve as a platform for generating hypotheses for future studies addressing genetic and immunological factors associated with susceptibility to VZV encephalitis. These data, taken together, suggest that disturbances in innate sensing and autophagy pathways may predispose to VZV encephalitis.
水痘带状疱疹病毒（VZV）感染可能涉及不同的中枢神经系统（CNS）表现，包括脑膜炎、脑炎和血管炎。在原本健康的个体受到影响的病例中，先天性免疫缺陷可能是感染易感性增加或病情严重程度增加的基础。
我们收集了一组17名患VZV脑炎的成年人，并进行了全外显子组测序。用VZV感染患者外周血单个核细胞，并评估先天性抗病毒干扰素（IFN）和细胞因子反应以及病毒复制情况。数据采用Mann-Whitney U检验进行分析。
在纳入的17例患者中的13例中，我们总共鉴定出21种不同的潜在致病变异。这些基因变异存在于2个主要功能簇中：（1）先天性病毒传感器和免疫途径，以及（2）自噬途径。大多数患者的抗病毒IFN和细胞因子反应异常，而17例患者中只有2例病毒复制增加。
本研究确定了一系列具有致病潜力的变异，这可能为未来研究与VZV脑炎易感性相关的遗传和免疫因素提供一个生成假设的平台。综合这些数据表明，先天性感知和自噬途径的紊乱可能易患VZV脑炎。
