Temporal Transcriptomics in Hospitalized COVID-19 Patients from Disparately Impacted Ancestral Groups for Therapeutic Discovery

项目总结 SARS-CoV-2是一种引起新冠肺炎的新型冠状病毒，目前已有4600万人感染该疾病 到2020年10月31日，印度将有120万人死亡。美国是全球病例数(920万例)和死亡率(23万例)最高的国家。 最近全国每天都有创纪录的病例和住院率。这一次尤其是 对于新墨西哥州来说是这样的，那里的病例和住院人数再次激增。现在人们认识到，某些人 少数群体，即非洲裔美国人、西班牙裔美国人和美国印第安人/阿拉斯加原住民(AI/AN)遭受损失 与新冠肺炎不成比例。北卡罗来纳州拥有最高比例的西班牙裔祖先，也是最大的 这两组病例分别占累计病例的47%和26%。之后 对人口规模进行调整后，AI/AN组的累积发病率高出3.3倍，高出7.9倍 住院人数增加，经年龄调整的死亡率增加10.6倍。作为唯一的学术医学中心和 在该州一级创伤中心，新墨西哥大学医院(UNH)发挥了主要作用 在护理新冠肺炎患者方面。联合国儿童基金会是新墨西哥州和周边地区的初级三级护理转诊中心。 各地区，包括纳瓦霍民族和其他部落土地。因此，我们具有得天独厚的优势 关于新冠肺炎疾病严重程度和死亡率增加的分子基础的重要知识差距 在受到不成比例影响的祖先群体中。2月中旬，新墨西哥大学全球卫生中心召集了一次 多学科调查小组，以应对新冠肺炎的挑战。截至10月31日，我们有 招募并跟踪167名新冠肺炎住院患者，为快速翻译提供机会 在计划的三年研究中产生的影响。实验策略与我们正在进行的R01研究在 非洲儿童利用信使核糖核酸序列识别新的治疗靶点(PI：Perkins)。最先进的 我们将应用实验室中的方法和建模工作来创建解决方案，以改进 新冠肺炎患者的预后。这将通过以下非严重和严重的新冠肺炎患者来实现 跨越不同祖先群体的住院，顺利完成三个具体目标：1)确定 SARS-CoV-2病毒载量动态对疾病严重性的影响，2)识别 调节疾病严重程度，以及3)确定FDA批准的调节基因网络的优先化合物 与增强的疾病严重性相关，用于未来的临床试验。在很短的时间内，我们已经产生了 关于病毒载量动态的大量数据，并通过目标化合物匹配确定了新的基因网络。我们 目前的数据显示，AI/AN血统的个体在 外周血和更严重的疾病，尽管与其他组有类似的共病因素。这个 拟议的调查具有直接的翻译影响，特别是对受不成比例影响的祖先 通过定义对SARS-CoV-2的宿主免疫反应，确定用于风险评估的生物标记物， 预测和疾病进展，促进药物再利用，以降低疾病严重程度和死亡率。

PROJECT SUMMARY SARS-CoV-2 is a novel coronavirus which causes COVID-19, a disease that has infected >46M people resulting in >1.2M deaths by 31 October 2020. The US has the highest global case count (>9.2M) and mortality (>230K) with recent record-setting daily cases and hospitalization rates across the country. This has been particularly true for New Mexico (NM) where cases and hospitalizations are surging again. It is now recognized that certain minority groups, i.e., African Americans, Hispanics, and American Indians/Alaska Natives (AI/AN), suffer disproportionally from COVID-19. NM has the highest proportion of Hispanic ancestry, and one of the largest AI/AN populations, with these two groups representing 47% and 26% of the cumulative cases, respectively. After adjusting for population size, the AI/AN group has 3.3-fold higher cumulative case rates, 7.9-fold higher hospitalizations, and 10.6-fold higher age-adjusted mortality rates. As the only academic medical center and Level 1 Trauma Center in the state, the University of New Mexico Hospital (UNMH) has played a principal role in caring for patients with COVID-19. UNMH is the primary tertiary care referral center for NM and surrounding regions, including the Navajo Nation and other tribal lands. As such, we are uniquely positioned to address important gaps-in-knowledge about the molecular basis of increased COVID-19 disease severity and mortality in disproportionally affected ancestral groups. In mid-February, the UNM Center for Global Health assembled a multidisciplinary group of investigators to address the challenges of COVID-19. As of 31 October, we have recruited and followed 167 hospitalized patients with COVID-19, offering an opportunity for rapid translational impact within the planned three-year study. The experimental strategy parallels our ongoing R01 studies in African children utilizing mRNA-Seq to identify novel therapeutic targets (PI: Perkins). State-of-the-art methodologies and modeling efforts in place in our laboratories will be applied to create solutions for improving outcomes in COVID-19 patients. This will be achieved by following non-severe and severe COVID-19 patients across hospitalization from different ancestral groups to successfully complete three specific aims: 1) determine the impact of SARS-CoV-2 viral load dynamics on disease severity, 2) identify gene expression networks that mediate disease severity, and 3) identify prioritized FDA-approved compounds that modulate gene networks associated with enhanced disease severity for use in future clinical trials. In a short time, we have generated extensive data on viral load dynamics and identified novel gene networks with target-compound matches. We present data showing that individuals of AI/AN descent have significantly higher and protracted viral loads in peripheral blood and more severe disease, despite comparable co-morbid factors with other groups. The proposed investigations have direct translational impact, particularly in disproportionately affected ancestral groups by defining the host immune response to SARS-CoV-2, identifying biomarkers for risk assessment, prognosis, and disease progression, and fostering drug repurposing to reduce disease severity and mortality.