Asthma Endotypes: Mechanisms and Consequences for Airway Epithelium and Mucus

项目摘要/摘要 新冠肺炎是由新型SARS-CoV-2病毒引起的大流行疾病，是一种严重的呼吸道疾病 具有很高的传染性，死亡率从1%到20%不等，具体取决于潜在的风险因素。 事实上，根据公认的临床风险因素(年龄和合并症)，疾病的严重程度明显不同。 这种临床变异的生物学基础尚不清楚，但可能与这两种病毒的变异有关。 和宿主的反应。详细了解严重疾病的风险因素，包括遗传和 环境因素和宿主的免疫反应的性质，是发展的关键 预测预后的生物标志物和有效的治疗方法。为了满足这一迫切需求，我们建议帮助开发和 参与新冠肺炎和TO住院患者的IMPACC多中心纵向临床研究 使用共享免疫学方法的免疫表型参与者将由以下人员设计和实施 加州大学旧金山分校和其他参与机构的核心实验室。我们的具体目标是1)开发一种 已知或推定住院的成人受试者的前瞻性观察方便性队列 新冠肺炎，2)使用这个队列来描述特定的免疫学评估和 新冠肺炎在住院患者中的临床进程，以及3)在加州大学旧金山分校实施三个核心实验室，以 在这个多中心队列中支持免疫表型。这些核心实验室将进行批量核糖核酸 外周血单个核细胞(PBMC)测序，批量元基因组下一代 气管内抽吸物样本测序(MNGS)和血清学噬菌体展示分析(PhIP-Seq)。 这些目标的成功完成将产生关于病毒载量和病毒载量之间关系的关键信息， 宿主免疫反应和临床预后差，迫切需要生物标志物 发展和合理的治疗靶向。此外，这项研究中储存的细胞样本可能 直接促进中和抗体和疫苗战略的发展，这将是我们的终极目标 防范这场非同寻常的大流行重演。快速而有力的科学和医学反应 由NIAID和该联盟中的学术界提出的类型是 为保护所有人的健康和福祉、我们的卫生保健系统和 维护全球健康和福利的更广泛的社会结构。

PROJECT SUMMARY/ABSTRACT COVID-19, the pandemic illness caused by the novel virus SARS-CoV-2, is a serious respiratory illness that has high infectivity and a mortality rate that varies from <1% to up to 20% depending on underlying risk factors. Indeed, disease severity varies markedly based on recognized clinical risk factors (age and co-morbidities). The biological underpinnings of this clinical variability are unknown but likely relate to variation in both the virus and the host response. A detailed understanding of the risk factors for severe disease, including genetic and environmental factors and the nature of the host immunological response, is essential for the development of prognostic biomarkers and effective therapies. To meet this urgent need we propose to help develop and to participate in the IMPACC multi-center longitudinal clinical study of hospitalized patients with COVID-19 and to immunophenotype participants using shared immunological methods that will be designed an carried out by core laboratories at UCSF and at other participating institutions. Our specific aims are 1) to develop a prospective observational convenience cohort of adult subjects hospitalized with known or presumptive COVID-19, 2) to use this cohort to describe the relationship between specific immunologic assessments and clinical course of COVID-19 in hospitalized patients, and 3) to implement three core laboratories at UCSF to support immunophenotyping in this multicenter cohort. These core laboratories will perform bulk RNA sequencing of blood peripheral blood mononuclear cells (PBMC), bulk metagenomic next-generation sequencing (mNGS) on endotracheal aspirate samples, and serologic phage display assays (PhIP-Seq). Successful completion of these aims will yield critical information regarding the relationship between viral load, host immunological responses, and poor clinical outcomes that are urgently needed for biomarker development and rational therapeutic targeting. In addition, the cellular samples banked in this study may directly contribute to the development of neutralizing antibodies and vaccine strategies that will be our ultimate defense against recurrence of this extraordinary pandemic. A rapid and robust scientific and medical response of the type proposed by the NIAID and the academic community in this consortium is an essential element of a broad response required to protect the health and well-being of all individuals, our health care system, and the broader social structures that maintain global health and welfare.