Abstract：
Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient\'s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient\'s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.
摘要：
人类疱疹病毒-6（HHV-6）感染很少会导致危及生命的疾病，比如脑炎，在其他健康的孩子身上，发病机制不清楚。我们研究了一名儿童，该儿童在10个月大时患有急性HHV-6脑炎，并且在IRAK4中具有纯合子，该突变编码白介素-1受体相关激酶4，通过全外显子组测序鉴定。我们通过分子动力学模拟和利用细胞系和患者细胞的生化和功能实验在体外测试了这种突变的破坏性影响。我们发现突变是严重的双态,损害IRAK-4的表达和功能。患者的白细胞几乎检测不到IRAK-4水平，并且对诱导不同Toll样受体和胞质核酸传感器的各种刺激的抗病毒免疫反应减弱。总的来说,这些发现提示急性HHV-6脑炎可能是由于对病毒的先天免疫错误所致.这项研究代表了在遗传性原发性免疫缺陷中引起脑炎的孤立性急性HHV-6感染的第一份报告。特别是常染色体隐性遗传（AR）部分IRAK-4缺乏症，以及首次报告出现严重病毒性疾病的ARIRAK-4缺乏症，特别是急性感染时的HHV-6脑炎，从而扩大IRAK-4缺乏症的临床范围。
