Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2

ASBTRACT概述 每天，加州人都会继续经历新的严重急性呼吸道疾病的高水平暴露 冠状病毒2型(SARS-CoV-2)病毒。人们越来越迫切地需要更好地了解 暴露、病程和康复，以及特别高的人的免疫力潜力 新冠肺炎最糟糕结果的风险。作为对当前公共卫生危机的快速科学反应的一部分， 我们于2020年3月18日召集了一线临床医生和科学家共同组成了冠状病毒风险 协会和纵向评估(Corale)研究(Corale-Study.org)。我们建立了两个基础研究 登记的队列集中在(I)疑似或确诊为新冠肺炎的患者在我们的健康状况下接受治疗 系统(目前为N&GT；8,300)和(Ii)直接或间接参与提供护理的医护人员 (目前N=6,679)。作为对NIH RFA-CA-20-038的回应，我们现在非常有动力，并准备利用 我们现有的基础设施可直接满足全面纵向数据收集和 分析以提高我们对SARS-CoV-2风险、病程、康复性质、 以及在高危人群中产生免疫力的可能性。通过建立Corale-SeroNet U54计划， 我们的目标将是形成一个强大和可持续的学术活动结构，以调查 SARS-CoV-2暴露引起的反应以及仔细表型的临床和分子程度 轮廓可以标志着强大的免疫重建和完全的功能恢复。我们的研究将以 关于洛杉矶卫生系统服务的种族/种族多元化人口，考虑到当时的迫切需要 了解更多有关这些少数群体新冠肺炎相关风险决定因素的信息。我们的 科学目标将通过一个由临床医生-科学家、流行病学家、 免疫学家、基础科学家和翻译科学家、分析化学家和生物统计学家。利用我们的 南方各大学术机构的集体经验、资源和基础设施 加利福尼亚州(雪松西奈、加州大学洛杉矶分校、加州大学洛杉矶分校和南加州大学)，我们将通过这三个项目推进科学事业 不同但紧密结合的研究项目：项目1将阐明自然历史和纵向 代表SARS-CoV-2暴露、感染、康复和临床免疫多样性的轨迹 所有处于危险中的人的模式。项目2将调查SARS-CoV-2的决定因素 先天免疫功能改变者的反应，重点是感染前的个体 易感性特征(例如代谢性疾病状态)；项目3将调查SARS的决定因素- 获得性免疫功能改变的人群中的CoV-2应答，重点关注免疫- 因特定的恶性肿瘤、自身免疫性疾病和/或其定向治疗而引起的状态改变。作为一个整体 这一研究计划将把人口、临床、翻译和基础科学资源与世界- 一流的研究团队，以满足对新的机械洞察力和治疗方法的迫切需求 解决有关SARS-CoV-2易感性和免疫潜力的关键知识空白。

ASBTRACT Overview Every day, Californians continue to experience high levels of exposure to the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature of exposures, course of illness and recovery, and potential for immunity among persons at particularly heightened risk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisis, we convened on March 18, 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus Risk Associations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base study cohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our health system (currently N>8,300) and on (ii) healthcare workers directly or indirectly involved in delivering their care (currently N=6,679). In response to NIH RFA-CA-20-038, we are now highly motivated and prepared to leverage our existing infrastructure to directly address the critical need for comprehensive longitudinal data collection and analyses to advanced our understanding of SARS-CoV-2 risks, the course of disease, the nature of recovery, and the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 program, our goal will be to form a robust and sustainable structure of academic activities centered on investigating the responses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecular profiles can signal robust immune reconstitution and complete functional recovery. Our study will be centered on the ethnically/racially diverse population served by our health system in Los Angeles, given then critical need for more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Our scientific objectives will be achieved by an outstanding collaborative team of clinician-scientists, epidemiologists, immunologists, basic and translational scientists, analytical chemists, and biostatisticians. Leveraging our collective experience, resources, and infrastructure at major academic institutions from across Southern California (Cedars Sinai, UCSD, UCLA, and USC), we will advance the scientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure, infection, recovery, and clinical immunity patterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2 response in persons with altered innate immune function, with a focus on individuals with pre-infection susceptibility traits (e.g. metabolic disease states); and, Project 3 will investigate the determinants of SARS- CoV-2 response in persons with altered adaptive immune function, with a focus on individuals with immune- altered status arising from select malignancies, autoimmune disease, and/or their directed therapies. As a whole this research program will integrate population, clinical, translational, and basic science resources with a world- class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches to address key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity.