Genetic and immunological dissection of isolated Nocardiosis

分离诺卡氏菌病的遗传和免疫学解剖

• 批准号: 10510731
• 负责人: Ruben Martinez Barricarte
• 金额: $ 21.63万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510731
• 关键词: Antibodies; Antibody Specificity; Antibody titer measurement; Antibody-mediated protection; Autoantibodies; Autoimmunity; Basic Science; Biological; Case Study; Cells; Chronic Granulomatous Disease; Clinical; Communicable Diseases; Computing Methodologies; Coupled; Cytometry; Data; Defect; Disease; Dissection; Epidemic; Exposure to; Family; Frequencies; Future; General Population; Genes; Genetic; Genetic Counseling; Gram-Positive Bacteria; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Infections; Hereditary Disease; Human; Human Genetics; Iatrogenesis; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Immunosuppression; Impairment; Individual; Infection; Inherited; Knowledge; Light; Molecular; Molecular Biology; Molecular Diagnosis; Mutate; Mutation; Nocardia; Nocardia Infections; Outcome; Pathway interactions; Patients; Persons; Phagocytes; Phenotype; Physicians; Play; Population Genetics; Predisposition; Prevalence; Preventive; Preventive therapy; Rare Diseases; Reactive Oxygen Species; Reporting; Risk; Risk Factors; Role; Seeds; Severe Combined Immunodeficiency; System; T-Lymphocyte; Testing; Therapeutic; Translating; Work; acquired immunodeficiency; cell type; cofactor; cohort; computerized tools; congenital immunodeficiency; cytokine; disease-causing mutation; exome sequencing; fighting; genetic analysis; genetic architecture; genetic disorder diagnosis; impaired capacity; novel; pathogen; predictive tools; prevent; recruit; targeted treatment

PROJECT SUMMARY Nocardiosis is a severe infectious disease caused by the gram-positive bacteria Nocardia spp. Although exposure to the pathogen is universal, only a small fraction of exposed individuals develop severe disease. The observation that the epidemic (HIV infection) and iatrogenic (T cell immunosuppression) forms of nocardiosis are due to acquired immunodeficiency suggests that nocardiosis in otherwise healthy individuals may be due to inherited immunodeficiency. Further strengthening this point, patients with some primary immunodeficiencies (PIDs) such as chronic granulomatous disease (CGD)1–5, severe combined immunodeficiency (SCID)6, or hypogammaglobulinemia 7,8 develop nocardiosis. Hence, we hypothesize that nocardiosis in otherwise healthy individuals is an undiagnosed PID. We have recruited a growing cohort of patients without any detectable risk factors that develop severe nocardiosis to test this hypothesis. Furthermore, we have performed whole-exome sequencing (WES) in these patients and found that all the genes described to cause a PID are wild type suggesting that inborn errors of immunity in additional genes may account for nocardiosis in some of these patients. Interestingly, we have found that one-fifth of our patients carry neutralizing anti-GM-CSF auto- antibodies confirming that exposure to Nocardia spp. is necessary. Still, a permissive immune state of the host is required to develop the diseases. Therefore, this proposal aims to understand the genetic and immunological components of nocardiosis by using two complementary approaches. In our first specific aim, we will use a systems immunology approach to identify immunological abnormalities in the patients, such as the presence of auto-antibodies against cytokines, antibody deficiencies, or reduced frequencies of individual immune cells. We will gain valuable information regarding the pathways and cell types involved in anti-Nocardia immunity by performing these analyses. In our second specific aim, we will mine the WES data from the patients in search of new inborn errors of immunity. To this end, we will perform a genetic analysis combining population genetics, gene-level, and mutation-level predictive tools to identify mutations that can explain isolated nocardiosis. The work proposed in this application has far-reaching clinical and biological implications since it will seed light into the immune and genetic mechanisms critical to fending off Nocardia spp. Biologically, by studying patients with this rare disease, we will gain basic immunology knowledge of the vital and non-redundant roles of specific cell types, molecules, and pathways for the proper assembly of human immune responses. Clinically, this immunological knowledge could be translated into therapies for more common diseases, as has been the case by studying other PIDs9. Furthermore, our work will pave the way to provide genetic counseling and diagnosis to patients and families and propose preventive or targeted therapies for individuals at risk. Our proposal highlights the power of studying rare diseases for the basic and translational information that their study offers.

项目摘要 诺卡氏菌病是由革兰氏阳性菌诺卡氏菌引起的一种严重的传染病。虽然 由于接触病原体是普遍的，只有一小部分接触者会发展成严重的疾病。的 观察到流行性（HIV感染）和医源性（T细胞免疫抑制）形式的诺卡氏菌病 是由于获得性免疫缺陷，表明诺卡菌病在其他健康的个人可能是由于 遗传性免疫缺陷进一步加强这一点，一些原发性免疫缺陷患者 （PID），如慢性肉芽肿病（CGD）1-5，严重联合免疫缺陷（SCID）6，或 低丙种球蛋白血症7、8发展为诺卡氏菌病。因此，我们假设，在其他健康的人中， 这是一个未确诊的PID。我们招募了越来越多的没有任何可检测风险的患者 发展严重诺卡氏菌病的因素来验证这一假设。此外，我们进行了全外显子组 在这些患者中进行了WES测序，发现所有被描述为导致PID的基因都是野生型 这表明，在其他基因中的先天性免疫缺陷可能是其中一些人患诺卡氏菌病的原因。 患者有趣的是，我们发现五分之一的患者携带中和性抗GM-CSF自动抗体， 抗体证实暴露于诺卡氏菌属是必要的.尽管如此，一个允许的免疫状态的主机 是疾病发展所必需的。因此，这项建议旨在了解遗传和免疫学 通过使用两种互补的方法来分析诺卡氏菌病的组成部分。在我们的第一个具体目标中，我们将使用 系统免疫学方法，以确定患者的免疫异常，如是否存在 针对细胞因子的自身抗体、抗体缺陷或个体免疫细胞频率降低。我们 将获得有关参与抗诺卡氏菌免疫的途径和细胞类型的宝贵信息， 进行这些分析。在我们的第二个具体目标中，我们将从患者中挖掘WES数据， 新的先天性免疫缺陷为此，我们将结合群体遗传学进行遗传分析， 基因水平和突变水平的预测工具，以确定突变，可以解释孤立的诺卡氏菌病。的 这项应用中提出的工作具有深远的临床和生物学意义，因为它将把光种子植入到 免疫和遗传机制的关键抵御诺卡氏菌属。从生物学上讲，通过研究患有 这种罕见的疾病，我们将获得特定细胞的重要和非冗余作用的基本免疫学知识， 类型，分子和途径，为人类免疫反应的正确组装。临床上，这 免疫学知识可以转化为更常见疾病的治疗方法， 通过研究其他PIDs 9.此外，我们的工作将为提供遗传咨询和诊断铺平道路 向患者和家庭提供咨询，并为有风险的个人提出预防或靶向治疗。我们的建议 强调了研究罕见疾病的力量，因为他们的研究提供了基本和翻译信息。