Genetic and Epigenetic Programming of Allergic Airway Inflammation

过敏性气道炎症的遗传和表观遗传编程

基本信息

批准号：
10169796
负责人：
Talal Amine Chatila
金额：
$ 12.76万
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：
2020-06-12 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10169796
关键词：
2019-nCoV Adult Respiratory Distress Syndrome Affect Air Pollution Allergens Antiviral Agents Blood specimen CCL2 gene CCL3 gene CD8-Positive T-Lymphocytes COVID-19 CXCL10 gene Cells Clinical Critical Care Critical Illness Development Diabetes Mellitus Disease Environmental Exposure Epigenetic Process Failure Floor Funding Genetic Hospitals Hypertension Immune Immune Tolerance Immune response Immune system Immunomodulators Inflammation Inflammatory Inpatients Interferon Type I Interleukin 6 Receptor Interleukin-2 Interleukin-6 Licensing Life Lung Lymphopenia Measures Mediating Memory Molecular Monoclonal Antibodies Monoclonal Antibody Therapy Morbidity - disease rate Multi-Drug Resistance Mus NOTCH4 gene Natural Immunity Obesity Outcome Particulate Matter Pathogenesis Pathogenicity Pathway interactions Patients Precision therapeutics Prevalence Process Proteins Regulation Regulatory Pathway Regulatory T-Lymphocyte Reporting Research Research Personnel Risk Role Severities Severity of illness Steroids T-Lymphocyte Testing Tissues Transcription Alteration Virus Replication Work adaptive immune response adaptive immunity airway inflammation allergic airway inflammation asthmatic bacterial resistance comorbidity coronavirus disease cytokine cytokine release syndrome effective therapy effector T cell epidemiologic data exhaustion functional restoration immunological status immunomodulatory therapies interest mortality multidisciplinary novel novel coronavirus patient subsets peripheral blood response superinfection

项目摘要

ABSTRACT This supplement was written in response to the original NOT-AI-20-031: Notice of Special Interest (NOSI): Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19), and submitted under PA-18-591]. COVID19, caused by the betacoronavirus clade SARS-CoV-2, ranges from asymptomatic disease to fatal multi-organ failure. Both innate and T cell-mediated adaptive immunity are important for limiting viral replication. Nevertheless, hyperactivation of the immune response in patients with more severe disease may precipitate a “cytokine storm” that results in aggravated morbidity and high mortality. Relevant to the role of immune hyperactivation in COVID disease pathogenesis are our recent studies on asthmatic inflammation showing how allergens and air pollution particulate matter (PM) overcome immune tolerance mechanisms operating in the airway to license tissue inflammation. We identified the JAG1-NOTCH4 axis as a key pathogenic mechanism activated by the allergens and PM that acts as a molecular switch to break down immune tolerance in the lung and consequently promote inflammation. Along this mechanism we identified that NOTCH4 was selectively induced on lung Treg cells in an allergen and interleukin-6 (IL-6)-dependent manner, and it directed their subversion into Th2/Th17 effector-like T cells. Importantly, our preliminary results reveal that NOTCH4 expression is upregulated on circulating Treg cells of COVID19 subjects as a function of disease severity, thus implicating this mechanism in disease pathogenesis in COVID19 subjects. Our central hypothesis is that dysregulation of innate and adaptive immunity in COVID19 involves the subversion of Treg cells in an IL-6 and NOTCH4-dependent manner. Our study team is composed of a multidisciplinary group of R01-funded investigators with prior collaborative work, clinical expertise in the care of critically ill COVID19 patients, and research expertise in the role of Treg cells in immunological tolerance. We propose to profile the innate and adaptive immune responses in subjects with mild-moderate and severe COVID19 disease as compared to convalescent and healthy control subjects. We will correlate these changes with NOTCH4 expression on circulating Treg cells and the latter’s immune regulatory functions. We will also examine the impact of Notch4 expression on transcriptional alterations in Treg and T effector cells in patients with COVID-19. Our studies offer a mechanistic approach to the elucidation of the enigma of immune hyperactivation in COVID19 and the promise to identify targets for precision therapy in this disease.

抽象的本补充是为了回应原始 NOT-AI-20-031：特别兴趣通知 (NOSI)：严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 和 2019 年冠状病毒病 (COVID-19)，并根据 PA-18-591 提交]，由 β 冠状病毒分支 SARS-CoV-2 引起，范围广泛。从无症状疾病到致命的多器官衰竭，先天免疫和 T 细胞介导的适应性免疫都是如此。然而，对于限制病毒复制很重要。更严重的疾病可能会引发“细胞因子风暴”，导致发病率上升和死亡率升高。与免疫过度激活在新冠病毒疾病发病机制中的作用相关的是我们最近的研究哮喘炎症显示过敏原和空气污染颗粒物 (PM) 如何克服免疫我们确定了 JAG1-NOTCH4 在气道中发挥作用以许可组织炎症。轴作为由过敏原和 PM 激活的关键致病机制，充当分子开关来打破降低肺部的免疫耐受性，从而促进炎症。 NOTCH4 在过敏原和白细胞介素 6 (IL-6) 依赖性的肺 Treg 细胞上选择性诱导重要的是，我们的初步结果表明它们会颠覆 Th2/Th17 效应样 T 细胞。揭示了 COVID19 受试者循环 Treg 细胞中 NOTCH4 表达上调，作为疾病的严重程度，从而暗示这种机制与我们的核心受试者的疾病发病机制有关。假设是，COVID19 中先天性和适应性免疫的失调涉及到颠覆 Treg 细胞以 IL-6 和 NOTCH4 依赖的方式进行我们的研究团队由多学科组成。由 R01 资助的研究人员组成的小组，他们之前有过合作工作，具有危重疾病护理方面的临床专业知识 COVID19 患者以及 Treg 细胞在免疫耐受中的作用的研究专业知识。分析轻度至中度和重度 COVID19 疾病受试者的先天性和适应性免疫反应与恢复期和健康对照受试者相比，我们将这些变化与 NOTCH4 相关联。我们还将研究其对循环 Treg 细胞的表达及其免疫调节功能的影响。 Notch4 表达对 COVID-19 患者 Treg 和 T 效应细胞转录变化的影响。研究为阐明新冠病毒免疫过度激活之谜提供了一种机制方法以及确定该疾病精准治疗靶点的承诺。