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

• 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
• 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

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.

摘要 本补充材料是针对原始NOT-AI-20-031：特别关注通知（NOSI）编写的： 严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）和2019冠状病毒病（COVID-19）， 并根据PA-18-591提交]。COVID 19由β冠状病毒分支SARS-CoV-2引起， 从无症状疾病到致命的多器官衰竭先天性和T细胞介导的适应性免疫都是 对限制病毒复制很重要。尽管如此，在患有糖尿病的患者中， 更严重的疾病可能引发“细胞因子风暴”，导致发病率加重和死亡率高。 与免疫超活化在COVID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 在气道中操作以许可组织炎症的耐受机制。我们发现了JAG 1-NOTCH 4 轴作为一个关键的致病机制激活的过敏原和PM，作为一个分子开关，打破 降低肺部的免疫耐受性，从而促进炎症。我们沿着这个机制确定了 在过敏原和白细胞介素-6（IL-6）依赖性免疫反应中， 并将其颠覆为Th 2/Th 17效应样T细胞。重要的是，我们的初步结果 揭示了COVID 19受试者的循环Treg细胞上的NOTCH 4表达上调，作为以下的函数： 疾病严重程度，因此在COVID 19受试者的疾病发病机制中涉及该机制。我们的中央 假设是COVID 19中先天性和适应性免疫的失调涉及 Treg细胞以IL-6和N 0 TCH 4依赖性方式表达。我们的研究团队由多学科组成， 一组由R 01资助的研究人员，他们之前曾进行过合作，在危重病护理方面具有临床专业知识， COVID 19患者，并研究Treg细胞在免疫耐受中的作用。我们建议 描述轻度-中度和重度COVID 19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NOTCH 4 在循环Treg细胞上的表达和后者的免疫调节功能。我们还将研究其影响 Notch 4表达对COVID-19患者Treg和T效应细胞转录改变的影响。我们 研究为阐明COVID 19中免疫过度激活之谜提供了一种机制方法 以及确定这种疾病精确治疗靶点的希望。