Inborn errors of immunity in children with herpes simplex encephalitis

单纯疱疹脑炎患儿先天性免疫缺陷

• 批准号: 10377908
• 负责人: Jean-Laurent Casanova
• 金额: $ 51万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377908
• 关键词: Acyclovir; Affect; Alleles; Architecture; Biochemical; Brain Stem; Candidate Disease Gene; Cells; Child; Childhood; Clinical; Collection; Communicable Diseases; Complication; Country; Data; Disease; Encephalitis; Enrollment; Family; Fibroblasts; Funding; Genes; Genetic; Genetic Counseling; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic study; Genotype; Hereditary Disease; Herpes encephalitis; Herpesvirus 1; Heterogeneity; Human Genetics; IFNAR1 gene; IRF3 gene; Immunity; Immunologics; Impairment; Individual; Infection; Interferon-alpha; Interferons; International; Laboratories; Lesion; Leukocytes; Life; Mediating; Mendelian disorder; Minority; Modeling; Molecular; Molecular Diagnosis; Molecular Genetics; Mutation; Neuraxis; Neurologic; Neurons; Olfactory Nerve; Organ; Parents; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Physiological; Population; Primary Infection; Privatization; Prosencephalon; RIPK1 gene; RIPK3 gene; Research; Resistance; Solid; Survivors; TBK1 gene; TLR3 gene; TNF receptor-associated factor 3; Techniques; Testing; Trigeminal nerve structure; United States National Institutes of Health; Validation; Variant; Viral Encephalitis; Work; base; candidate selection; clinical care; cohort; congenital immunodeficiency; design; exome sequencing; genetic analysis; genetic linkage analysis; genome sequencing; genome-wide; genome-wide linkage; induced pluripotent stem cell; innovation; kindred; mutant; next generation sequencing; novel; novel therapeutic intervention; recruit; response; trait; transcriptome sequencing; whole genome

Project Summary Childhood herpes simplex encephalitis (HSE) is a life-threatening complication of primary infection with herpes simplex virus 1 (HSV-1), which is typically innocuous. Acyclovir-treated survivors often suffer from severe neurological sequelae. Most infections affect the forebrain, with only a minority affecting the brainstem. HSE is the most common sporadic viral encephalitis in Western countries. Its pathogenesis remained unclear until we showed that it results, in some children, from single-gene inborn errors of immunity to HSV-1 in the central nervous system (CNS). Using a candidate gene approach, we and others discovered the first six genetic etiologies of forebrain HSE: mutations of TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3. These disorders impair TLR3-dependent, IFN-α/β- and IFN-l-mediated, cell-intrinsic immunity in iPSC-derived cortical neurons. With NIH R01AI088364 funding, we initiated a genome-wide approach to search for novel HSE-causing genes by a combination of genome-wide linkage (GWL) analysis and whole-exome sequencing (WES). This led to the discovery of 1) a novel genetic etiology of forebrain HSE, SNORA31 mutations, and 2) the first genetic etiology of brainstem HSE, DBR1 mutations. Both disorders impair cell-intrinsic immunity to HSV-1 by novel mechanisms, independent of TLR3. No genetic etiology has yet been identified for 258 of the 280 HSE patients studied. We now hypothesize that 1) other single-gene inborn errors of CNS-intrinsic immunity to HSV-1 can underlie HSE, and 2) mutations affecting different pathways are responsible for forebrain and brainstem HSE. In the work proposed in this renewal application, we will use next-generation sequencing (NGS), including WES, whole- genome sequencing (WGS), and RNA-seq, to search for novel genetic etiologies of HSE. We will analyze the NGS data at both the population and patient levels, following both a candidate gene approach and an unbiased hypothesis-generating approach. We will consider models based on both genetic homogeneity and genetic heterogeneity, while also testing both physiological homogeneity (HSE-causing genes being physiologically related) and heterogeneity (different pathways involved), making use of novel computational approaches. We will analyze the function of mutant alleles of candidate genes. We will also use the patients’ fibroblasts to investigate the impact of the candidate genotypes on anti-HSV-1 immunity. This application is innovative but supported by exciting preliminary data. We have established a unique international cohort of 450 HSE children and intend to enroll at least 600 patients. From the WES data for the first 280 patients, we have already identified biallelic mutations of MEX3B and IFNAR1 (in the TLR3-IFN-a/b circuit), RIPK1 and RIPK3 (in the TLR3- necroptosis pathway), and TMEFF1 (defining a novel pathway). Our research will decipher the pathogenesis of a devastating pediatric illness, paving the way for new therapeutic approaches. The genetic analysis of HSE will also provide proof-of-principle that sporadic, life-threatening infectious diseases striking an isolated organ in otherwise healthy children can result from single-gene inborn errors of non-hematopoietic cell-intrinsic immunity.

项目摘要 儿童疱疹单纯脑炎（HSE）是一种威胁生命的原发性感染并发症 单纯形病毒1（HSV-1），通常是无害的。经有关cl维氏治疗的幸存者经常患有严重 神经后遗症。大多数感染会影响前脑，只有少数影响脑干。 HSE是 西方国家最常见的零星病毒脑炎。它的发病机理一直不清楚，直到我们 表明在某些孩子中，从单基因天生的免疫力到中央的HSV-1结果 神经系统（CNS）。使用候选基因方法，我们和其他人发现了前六个通用 前脑HSE的病因：TLR3，UNC93B1，TRIF，TRAF3，TBK1和IRF3的突变。这些疾病 损害TLR3依赖性，IFN-α/β-和IFN-L介导的细胞中性免疫组织化学神经元。 使用NIH R01AI088364资金，我们启动了全基因组的方法来搜索新型HSE引起的基因 通过全基因组链接（GWL）分析和全外观测序（WES）的结合。这导致了 发现1）前脑HSE，SNORA31突变的新型遗传病因和2）第一个遗传病因 脑干HSE，DBR1突变。两种疾病都通过新机制损害了对HSV-1的细胞中性免疫， 独立于TLR3。在280名HSE患者中，尚未确定258名遗传病因。我们 现在假设1）其他中枢神经系统中心免疫对HSV-1的免疫力可能是HSE的基础， 2）影响不同途径的突变负责前脑和脑干HSE。在工作中 在此续订应用中提出的建议，我们将使用下一代测序（NGS），包括WES，全部 基因组测序（WGS）和RNA-Seq，以搜索HSE的新遗传病因。我们将分析 遵循候选基因方法和公正的人口和患者水平的NGS数据 假设生成方法。我们将考虑基于遗传均匀性和遗传的模型 异质性，同时还测试了两个物理均匀性（引起HSE的基因在物理上 相关）和异质性（涉及不同的途径），利用新颖的计算方法。我们 将分析候选基因突变等位基因的功能。我们还将使用患者的成纤维细胞 研究候选基因型对抗HSV-1免疫史的影响。该应用程序是创新的，但是 由令人兴奋的初步数据支持。我们已经建立了一个独特的国际队列，由450名HSE儿童组成 并打算注册至少600名患者。从前280名患者的WES数据中，我们已经确定了 MEX3B和IFNAR1的双重突变（在TLR3-IFN-A/B电路中），RIPK1和RIPK3（在TLR3-中 坏死途径）和TMEFF1（定义新的途径）。我们的研究将破译 一种毁灭性的小儿疾病，为新的治疗方法铺平了道路。 HSE的遗传分析将 还提供原理证明，零星，威胁生命的感染性疾病袭击了孤立的器官 否则，健康的儿童可能是由非杂造细胞中性免疫的单基因天生误差引起的。