Genetic and Epigenetic Programming of Allergic Airway Inflammation

摘要 本附录是针对最初的NOT-AI-20-031：特别关注通知(NOSI)编写的： 严重急性呼吸系统综合症冠状病毒2(SARS-CoV-2)和冠状病毒病2019(新冠肺炎)， 并根据PA-18-591提交]。由贝塔冠状病毒分支SARS-CoV-2引起的COVID19病毒范围 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 对限制病毒复制很重要。然而，慢性阻塞性肺疾病患者的免疫反应过度激活 更严重的疾病可能会引发一场“细胞因子风暴”，导致更严重的发病率和高死亡率。 与免疫过度激活在COVID疾病发病机制中的作用相关的是我们最近对 哮喘炎症显示过敏原和空气污染颗粒物(PM)如何战胜免疫 耐受机制在呼吸道中运行，以许可组织炎症。我们鉴定了JAG1-NOTCH4 AXIS是一种关键的致病机制，由过敏原和PM激活，起到分子开关的作用 降低肺部的免疫耐受性，从而促进炎症。根据这一机制，我们确定了 NOTCH4在依赖变应原和白介素6的肺Treg细胞上的选择性诱导 方式，并将其颠覆为Th2/Th17效应型T细胞。重要的是，我们的初步结果 COVID19受试者循环Treg细胞上NOTCH4表达上调 疾病的严重性，从而在COVID19受试者的疾病发病机制中牵涉到这一机制。我们的中央 假设COVID19先天免疫和获得性免疫的失调涉及颠覆 以IL-6和NOTCH4依赖的方式诱导Treg细胞。我们的学习团队是由一个多学科的 由R01资助的研究人员小组，在危重患者的护理方面具有先前的协作工作和临床专业知识 COVID19患者，以及对Treg细胞在免疫耐受中的作用的研究专长。我们建议 轻、中、重度冠状病毒病患者的先天和获得性免疫反应 与康复期和健康对照组比较。我们将把这些变化与NOTCH4相关联 循环Treg细胞的表达及其免疫调节功能我们还将研究其影响 新冠肺炎患者Treg和T效应细胞Notch4表达的转录变化我们的 研究为阐明COVID19免疫过度激活之谜提供了一种机制途径 以及确定精确治疗这种疾病的靶点的承诺。

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.