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

ASBTRACT概述 每一天，加州人继续经历高水平的接触到新的严重急性呼吸道感染， 冠状病毒2（SARS-CoV-2）病毒。越来越迫切地需要更好地了解 接触、病程和恢复情况，以及特别高剂量人群的免疫潜力 最坏的COVID-19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的合作，以形成冠状病毒风险 协会和纵向评价（CORALE）研究（corale-study.org）。我们建立了两个基地研究 入组队列集中于（i）在我们的健康中心接受治疗的疑似或确诊COVID-19患者 系统（目前N> 8，300）和（ii）直接或间接参与提供护理的医疗保健工作者 （目前N = 6，679）。为了响应NIH RFA-CA-20 - 038，我们现在非常积极，并准备利用 我们现有的基础设施，以直接满足全面的纵向数据收集的关键需求， 分析，以提高我们对SARS-CoV-2风险，疾病过程，恢复的性质， 以及在高危人群中的免疫潜力。通过建立CORALE-SeroNet U54程序， 我们的目标将是形成一个强大的和可持续的学术活动结构，以调查为中心， SARS-CoV-2暴露引起的反应以及仔细分型临床和分子生物学的程度 特征谱可以表示稳健的免疫重建和完全的功能恢复。我们的研究将集中在 考虑到当时的迫切需要，我们在洛杉矶的卫生系统所服务的种族/种族多样化的人口 了解更多关于这些少数群体中COVID-19相关风险的决定因素。我们 科学目标将由临床科学家，流行病学家， 免疫学家、基础和转化科学家、分析化学家和生物统计学家。利用我们 南方主要学术机构的集体经验、资源和基础设施 加州（雪松西奈，加州大学圣地亚哥分校，加州大学洛杉矶分校，南加州大学），我们将通过三个推进科学事业 独特而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、恢复和临床免疫多样性的轨迹 各种高危人群的模式。项目2将研究SARS-CoV-2的决定因素 先天免疫功能改变的人的反应，重点是感染前的个体 易感性特征（例如代谢疾病状态）;以及，项目3将研究SARS的决定因素- 适应性免疫功能改变的人的CoV-2应答，重点是免疫功能改变的人。 由选定的恶性肿瘤、自身免疫性疾病和/或其定向治疗引起的改变的状态。整个 该研究计划将整合人口，临床，转化和基础科学资源， 类研究者团队，以满足新的机制见解和治疗方法的迫切需要， 解决关于SARS-CoV-2易感性和免疫潜力的关键知识差距。

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.