Genetic and immunological dissection of isolated Nocardiosis

项目总结 诺卡氏菌病是由革兰氏阳性菌诺卡氏菌引起的一种严重传染病。虽然 接触这种病原体是普遍的，只有一小部分接触者会患上严重的疾病。这个 观察诺卡氏菌病的流行形式(艾滋病毒感染)和医源性(T细胞免疫抑制)形式 是由获得性免疫缺陷引起的，这表明在其他健康的人中，诺卡菌病可能是由于 遗传性免疫缺陷。进一步加强这一点，患有一些原发免疫缺陷的患者 (PID)，如慢性肉芽肿性疾病(CGD)1-5，严重联合免疫缺陷(SCID)6，或 低丙种球蛋白血症7，8发展为诺卡菌病。因此，我们假设诺卡氏菌病在其他方面是健康的 个人是一种未诊断的PID。我们招募了越来越多的患者，没有任何可检测到的风险 患上严重诺卡氏菌病的因素来验证这一假说。此外，我们还进行了全外显子组 对这些患者进行了测序(WES)，并发现所有被描述为导致产后出血的基因都是野生型 提示额外基因先天免疫缺陷可能是诺卡氏菌病的原因。 病人。有趣的是，我们发现五分之一的患者携带中和抗GM-CSF自动- 确认接触诺卡氏菌的抗体。是必要的。尽管如此，宿主的一种允许的免疫状态 是发展这些疾病所必需的。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，对诺卡氏菌病的组成部分进行评估。在我们的第一个特定目标中，我们将使用 系统免疫学方法，以确定患者的免疫异常，如存在 针对细胞因子的自身抗体、抗体缺陷或单个免疫细胞频率降低。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有价值的信息 进行这些分析。在我们的第二个具体目标中，我们将从搜索患者的WES数据中挖掘 新的先天免疫错误。为此，我们将结合种群遗传学进行遗传分析， 基因水平和突变水平的预测工具，以确定可以解释孤立诺卡氏菌病的突变。这个 这项申请中提出的工作具有深远的临床和生物学意义，因为它将为 抵御诺卡氏菌的关键免疫和遗传机制。从生物学上讲，通过研究患有 这种罕见的疾病，我们将获得基本的免疫学知识的重要和非多余的特定细胞的作用 正确组装人类免疫反应的类型、分子和途径。临床上，这是一种 免疫学知识可以转化为对更常见疾病的治疗，就像已经发生的情况一样 通过研究其他PID 9。此外，我们的工作将为提供遗传咨询和诊断铺平道路。 向患者和家属提供帮助，并为有风险的个人提出预防性或针对性治疗。我们的建议 强调研究罕见疾病的力量，以获得他们的研究提供的基本和翻译信息。

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.