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

• 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
• 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

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.

摘要 由冠状病毒SARS-CoV-2引起的COVID-19具有不可预测的临床过程， 严重急性呼吸道综合征（SARS）的无症状携带者。绝大多数年轻 个体具有无症状至中度的临床过程，但一部分患者发展为严重的 全身炎症反应。调节SARS-CoV-2免疫反应的遗传因素仍然存在 未定义。 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，9名严重COVID-19患者中有8名患有预先存在的淋巴细胞减少症， 自身免疫或低丙种球蛋白血症。4名中度COVID-19患者中， 免疫功能紊乱对其中一名严重COVID-19患者进行全外显子组测序， 可溶性CD 25水平升高鉴定了SOCS 1中的杂合移码突变（p.Ala9Profs），编码 细胞因子信号转导抑制因子1。预测该突变会导致SOCS 1单倍不足， 导致SOCS 1单倍不足小鼠模型中T细胞的过度活化。 SARS-CoV-2可能通过多种途径诱导内质网应激。几种病毒 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， 从高尔基体到内质网的运输，可能导致内质网应激。大量细胞因子分泌诱导ER 通过增加ER中新生蛋白质的负荷和细胞暴露于高水平的循环 细胞因子进一步增加ER应激。值得注意的是，严重COVID-19的临床表型与 在多微生物感染期间，在COPG 1突变小鼠中观察到，导致激活的 淋巴细胞 我们假设患有严重COVID-19的年轻个体表现出免疫失调， 对SARS-CoV-2感染的反应，以ER应激增加和淋巴细胞减少为特征 生存在AIM I中，我们将检验一个假设，即患有严重COVID-19的儿童在体内存在有害的变异， 调节抗病毒免疫和免疫稳态之间平衡的基因。在AIM II中，我们将测试 ER应激导致严重COVID-19特征性T细胞淋巴细胞减少的假设， 用TUDCA逆转。 拟议的研究有可能识别严重COVID-19的遗传变异， 从而影响疾病严重程度的重要途径。同时，我们对免疫细胞中ER应激的研究 来自COVID-19患者的研究将检验这一假设，即容易获得的ER压力缓解剂可能是 用于治疗COVID-19。