CORALE-SeroNet Project 1

摘要 紧迫的问题涉及到一贯观察到的关于宿主可变性质的悖论 对SARS-CoV-2的敏感性和反应。我们和其他人已经报道了更活跃的传播和更大的 老年人和少数民族/种族的发病率，特别是某些合并症和代谢。 到目前为止，迄今为止的证据表明，虽然有些人对SARS-CoV表现出特别的脆弱性， 2（即易感性），许多其他人对感染具有内在或获得性相对免疫力（即抵抗力 或疾病风险，或两者都有，原因不明。进一步加剧SARS-CoV-2风险的神秘性质是 关于免疫措施的相互矛盾的数据。我们和其他人发现， 对SARS-CoV-2表现出感染后IgG抗体反应的人是高度可变的-许多人没有 在症状消退后数周至数月内在外周循环中检测到抗体。我们 假设：（H1）对SARS-CoV-2暴露的自然反应史具有可辨别的模式 易感性与耐药性，因人口统计学、临床和宿主环境因素而异;以及（H2） 不同的临床轨迹是由复杂免疫系统中潜在的个体间差异驱动的， 对SARS-CoV-2暴露的炎症反应。根据早期的观察和新出现的数据，我们预计 接触者的四种潜在临床轨迹：（一）接触但显然没有感染的人; (ii)感染最小至无症状，然后持续免疫;（ii）感染有症状，恢复， 持续免疫;以及（iv）感染、恢复、再感染。为了验证这些假设，我们建议利用 我们现有的CORALE研究（n= 10，370）是一项在一个大都市进行的前瞻性纵向队列研究， 南加州的医疗保健系统。我们的服务区包括大量的西班牙裔/拉丁裔，黑人， 和亚洲人的年龄范围，代表高风险和研究不足的人群;反过来，我们的 卫生系统是全国治疗COVID-19患者数量最多的中心之一。我们的具体目标 是：（1）确定对SARS-CoV-2的易感性和免疫力的不同轨迹和决定因素;以及（2） 鉴定不同的免疫炎症特征（包括生物活性脂质类花生酸，急性期蛋白， 细胞因子及其衍生物）与SARS-CoV-2的易感性和免疫力相关。我们将使用两者 基线测量并进行系列SARS-CoV-2血清学测量（IgG + IgM），以纵向映射 血清学应答与临床和功能指标，并确定敏感性与 抵抗力（即对感染和疾病的脆弱程度、恢复速度和维持 对再感染或其他病毒性疾病如流感的合并感染的持久临床免疫力）。最后，我们将 按性别、年龄、种族/民族、社会经济地位和宿主环境检查轨迹的异质性 修饰因素（如吸烟、饮食和其他生活方式/行为因素）。CORALE-SeroNet项目1将确定 临床和分子特征表明， SARS-CoV-2暴露于多个不同人群，包括未充分研究的少数民族。

ABSTRACT Pressing questions pertain to the consistently observed paradoxes regarding the variable nature of host susceptibility and response to SARS-CoV-2. We and others have reported on more active spread and greater morbidity among older persons and ethnic/racial minorities, especially with certain comorbidities and metabolic. To date the evidence to date suggests that while some individuals exhibit a particular vulnerability to SARS-CoV- 2 (i.e. susceptibility), many others have an intrinsic or acquired relative immunity (i.e. resistance) to infection or disease risk or both for unknown reasons. Further compounding the enigmatic nature of SARS-CoV-2 risk is the conflicting data on measures of immunity. We and others have found that the extent to which individuals exhibit a post-infectious IgG antibody response to SARS-CoV-2 is highly variable – many persons have no antibodies detected in the peripheral circulation within weeks to months following resolution of symptoms. We hypothesize that: (H1) the natural history of response to SARS-CoV-2 exposure is marked by discernible patterns of susceptibility vs resistance that vary by demographic, clinical, and host-environment factors; and, (H2) divergent clinical trajectories are driven by underlying inter-individual differences in the complex immune- inflammatory response to SARS-CoV-2 exposure. Based on early observations and emerging data, we anticipate four potential clinical trajectories among exposed individuals: (i) those with exposure, but apparently no infection; (ii) infection with minimal to no symptoms, then persistent immunity; (ii) infection with symptoms, recovery, persistent immunity; and, (iv) infection, recovery, re-infection. To test these hypotheses, we propose to leverage our existing CORALE study (n=10,370), a prospective longitudinal cohort study at a major metropolitan healthcare system in Southern California. Our catchment area includes large numbers of Hispanic/LatinX, Black, and Asian individuals across the age range, representing high-risk and understudied populations; in turn, our health system is one of the nation’s highest volume centers for treating COVID-19 patients. Our specific aims are to: (1) identify distinct trajectories and determinants of susceptibility and immunity to SARS-CoV-2; and (2) identify distinct immune-inflammatory profiles (including bioactive lipid eicosanoids, acute phase proteins, cytokines, and their derivatives) associated with susceptibility and immunity to SARS-CoV-2. We will use both baseline measures and perform serial SARS-CoV-2 serologic measures (IgG + IgM) to longitudinally map serologic response with clinical and functional measures and define specific trajectories of susceptibility vs resistance (i.e. variations in degree of vulnerability to infection and illness, rate of recovery, and ability to maintain durable clinical immunity to re-infection or co-infection by other viral illnesses such as influenza). Lastly, we will examine heterogeneity in trajectories by sex, age, race/ethnicity, socioeconomic status, and host-environment modifiers (e.g. smoking, diet, and other lifestyle/behavioral factors). This CORALE-SeroNet Project 1 will identify the clinical and molecular profiles that signal robust immune reconstitution and functional recovery following SARS-CoV-2 exposure in multiple diverse populations including understudied minorities.