Mechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1

COPG1 纯合突变引起的新型联合免疫缺陷的机制

基本信息

批准号：
10159668
负责人：
RAIF SALIM GEHA
金额：
$ 38.98万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159668
关键词：
Activated Lymphocyte Age Age-Years Apoptosis Autoimmune Diseases Autoimmunity Back Bile Acids Binding Binding Proteins Biological Assay Boston C-terminal CISH gene COVID-19 Carrier State Cell Count Cell Death Cell physiology Cells Characteristics Chemicals Child Childhood Clinical Coat Protein Complex I Complex Data Disease model Endoplasmic Reticulum Equilibrium Exhibits Exposure to Failure Flow Cytometry Frameshift Mutation Genes Genetic Genetic Predisposition to Disease Golgi Apparatus Homeostasis IL2RA gene Immune Immune System Diseases Immune response Immunity Immunologic Deficiency Syndromes Impairment In Vitro Individual Infection Inflammatory Institutional Review Boards Intensive Care Units International Investigation Lymphocyte Lymphopenia Mediating Metabolic Molecular Chaperones Mononuclear Mus Mutant Strains Mice Mutation Output Pathway interactions Patients Pediatric Hospitals Peripheral Plasma Protein Secretion Proteins Recording of previous events Retrieval SARS coronavirus Sampling Severe Acute Respiratory Syndrome Severities Severity of illness Shapes Specialist Stress Symptoms T-Lymphocyte Technology Testing United States United States Food and Drug Administration Variant Viral Proteins Virus Diseases antiviral immunity candidate validation cholestatic liver disease clinical investigation clinical phenotype congenital immunodeficiency cytokine cytokine release syndrome endoplasmic reticulum stress exome exome sequencing genetic variant germ free condition hydrophilicity hypogammaglobulinemia member microbiota misfolded protein mouse model novel parent grant patient subsets protein folding protein transport recurrent infection retrograde transport single-cell RNA sequencing systemic inflammatory response tauroursodeoxycholic acid transcriptomics

项目摘要

Abstract COVID-19, caused by the coronavirus SARS-CoV-2, has an unpredictable clinical course ranging from an asymptomatic carrier state to severe acute respiratory syndrome (SARS). The vast majority of young individuals have an asymptomatic to moderate clinical course, but a subset of patients develop a severe systemic inflammatory response. The genetic factors regulating the immune response to SARS-CoV-2 remain undefined. Our preliminary data shows that since Boston Children’s Hospital began admitting patients with COVID- 19 in late March 2020, eight of nine of patients with severe COVID-19 had pre-existing lymphopenia, autoimmunity, or hypogammaglobulinemia. None of four patients with moderate COVID-19 had prior history of immune dysfunction. Whole exome sequencing on one of the patients with severe COVID-19 and extremely elevated soluble CD25 levels identified a heterozygous frameshift mutation (p.Ala9Profs) in SOCS1, encoding Suppressor of Cytokine Signaling 1. The mutation is predicted to result in SOCS1 haploinsufficiency, which results in overactivation of T cells in SOCS1 haploinsufficient mouse models. SARS-CoV-2 may induce endoplasmic reticulum (ER) stress through multiple pathways. Several viral proteins bind to ER resident proteins and to COPI, the heptameric complex that mediates retrograde protein trafficking from the Golgi to the ER, potentially causing ER stress. Massive cytokine secretion induces ER stress by increasing the load of nascent proteins in the ER, and cellular exposure to high levels of circulating cytokines further increases ER stress. Notably, the clinical phenotype of severe COVID-19 parallels that observed in COPG1 mutant mice during polymicrobial infection, resulting in increased ER stress in activated lymphocytes. We hypothesize that young individuals with severe COVID-19 exhibit a dysregulated immune response to SARS-CoV-2 infection, characterized by increased ER stress and reduced lymphocyte survival. In AIM I we will test the hypothesis that children with severe COVID-19 have deleterious variants in genes regulating the equilibrium between anti-viral immunity and immune homeostasis. In AIM II we will test the hypothesis that ER stress contributes to the T cell lymphopenia characteristic of severe COVID-19 and can be reversed with administration of TUDCA. The proposed studies have the potential for identification of genetic variants underlying severe COVID-19, and thereby pathways important for disease severity. In parallel, our investigations of ER stress in immune cells from patients with COVID-19 will test the hypothesis that readily available ER stress relieving agents may be useful for the treatment of COVID-19.

抽象的 COVID-19 由冠状病毒 SARS-CoV-2 引起，具有不可预测的临床病程，包括绝大多数年轻人是严重急性呼吸系统综合症（SARS）的无症状携带者。个体有无症状至中度临床病程，但一部分患者会出现严重的症状调节 SARS-CoV-2 免疫反应的遗传因素仍然存在。不明确的。我们的初步数据显示，自从波士顿儿童医院开始收治新冠肺炎患者以来， 2020 年 3 月下旬 19 日，9 名重症 COVID-19 患者中有 8 名先前存在淋巴细胞减少症，四名中度 COVID-19 患者均无既往病史。对一名重症 COVID-19 患者进行全外显子组测序。可溶性 CD25 水平升高鉴定出 SOCS1 中的杂合移码突变 (p.Ala9Profs)，编码细胞因子信号传导抑制因子 1。预计该突变会导致 SOCS1 单倍体不足，这导致 SOCS1 单倍体不足的小鼠模型中 T 细胞过度激活。 SARS-CoV-2 可能通过多种病毒途径诱导内质网 (ER) 应激。蛋白质与 ER 驻留蛋白和 COPI 结合，COPI 是介导逆行蛋白的七聚体复合物从高尔基体运输到内质网，可能导致内质网应激大量细胞因子分泌诱导内质网。通过增加内质网中新生蛋白的负载以及细胞暴露于高水平的循环液来缓解压力细胞因子进一步增加 ER 应激值得注意的是，重症 COVID-19 的临床表型与此相似。在多种微生物感染期间观察到 COPG1 突变小鼠，导致激活的内质网应激增加淋巴细胞。我们发现患有严重 COVID-19 的年轻人表现出免疫系统失调对 SARS-CoV-2 感染的反应，其特征是内质网应激增加和淋巴细胞减少在 AIM I 中，我们将检验患有严重 COVID-19 的儿童在基因中存在有害变异的假设。在 AIM II 中，我们将测试调节抗病毒免疫和免疫稳态之间平衡的基因。 ER 对严重 COVID-19 特有的 T 细胞淋巴细胞减少症产生应激的假设，并且可以通过给予 TUDCA 可以逆转。拟议的研究有可能识别严重的 COVID-19 背后的基因变异，同时，我们对免疫细胞中的内质网应激进行了研究。来自 COVID-19 患者的研究将检验以下假设：现成的 ER 应激缓解药物可能是可用于治疗 COVID-19。