BIOREPOSITORY OPTIMIZATION AND USE FOR ENDOTYPING CRITICALLY ILL SARS-COV-2 INFECTED PATIENTS

抽象的。纽约地区在美国早期就面临着新冠肺炎大流行的病例激增 导致多个卫生保健系统不稳定的国家，无法跟上对 危重护理使用率和死亡率。高死亡率的新冠肺炎危重病患者的异质性进化 而长时间在ICU的停留突显了更好地了解个人的内型可能暴露于 这些败血症患者的可治疗特征。当第一组病例到达纽约大学时，我们建立了一个生物信息库 这些SARS-CoV-2危重患者的下呼吸道样本和血液样本。我们有 已探索下呼吸道微生物环境，包括病毒体、细菌体和宿主免疫 回应。在我们最近的报告中，使用了142例危重患者新冠肺炎的下呼吸道横断面样本 发表在《自然微生物学》杂志上的患者，我们确定了与穷人相关的微生物和宿主特征 结果，主要由控制不佳的病毒复制、钝化的抗Spike/抗RBD免疫球蛋白反应驱动 和截然不同的宿主转录图谱。然而，为了了解这种糟糕的病毒背后的机制 我们需要对早期时间点的样本进行纵向研究。我们目前正在使用这些样本 描述病毒和宿主转录组的纵向动态。然而，关键的分子免疫 需要使用代谢组学方法来探索介质，而不同的细胞免疫反应可能 需要单细胞方法。在此应用程序中，我们将使用现有的生物存储库，并使用新的 用新的scRNA测序和序列分析来检验呼吸道和系统内型的假设的案例 代谢组学方法预测重症SARS-CoV-2患者的不良结局。因此，我们建议 扩大和优化我们的SARS-CoV-2危重患者呼吸道和系统样本生物库(R21 阶段)，以便执行scRNA测序和代谢组方法，以便对呼吸道进行内切型 和系统环境，以评估与不良临床结果的关联(R33阶段)。要完成 为了达到这些目标，我们将利用我们的专业知识来描述下呼吸道微生物群(包括病毒 部分)和宿主免疫简档。因此，这是一个前所未有的机会，进行必要的 新冠肺炎危重患者下呼吸道和全身配对标本的探索性研究 版面总结。急性新冠肺炎感染对人类健康造成前所未有的影响，病情危重 遭受高危重护理资源和高死亡率的患者。在这个项目中，我们将使用和扩展我们的 下呼吸道和血液样本的生物库，以探索确定分子特征的新方法 可以预测患者不良的临床结果。

Abstract. The New York City area has faced a surge of cases early on the COVID-19 pandemic in the United States leading to destabilization of multiple health care systems that could not keep up with the high demand for critical care use and mortality. The heterogenous evolution among critically ill COVID-19 patients, high mortality and prolonged ICU stay highlights the need to better understand individual’s endotype that could expose treatable traits among these septic patients. As the first set of cases arrived to NYU, we built a biorepository of samples from the lower airways and blood from these critically-ill SARS-CoV-2 infected patients. We have already explored the lower airway microbial environment including the virome, bacteriome and host immune response. In our recent report using cross sectional lower airway samples from 142 critically ill COVID-19 patients published in Nature Microbiology we identified microbial and host signatures associated with poor outcome, predominantly driven by poorly controlled viral replication, blunted anti-Spike/anti-RBD IgG response and distinct host transcriptomic profile. However, in order to understand the mechanism underlying this poor viral control we need to study samples at earlier time points and longitudinally. We are currently using these samples to characterize the longitudinal viral and host transcriptome dynamics. However, the critical molecular immune mediators need to be explored using metabolomic approaches while the distinct cellular immune responses may require single cell approaches. In this application we will use our existing biorepository and expand it with new cases to test the hypothesis that airway and systemic endotyping with novel scRNA sequencing and metabolomic approaches predicts poor outcome in critically ill SARS-CoV-2 patients. Thus, we propose to expand and optimize our biorepository of airway and systemic samples in critically ill SARS-CoV-2 patients (R21 phase) in order to perform scRNA sequencing and metabolomic approaches in order to endotype the airway and systemic environment to evaluate for associations with poor clinical outcome (R33 phase). To accomplished these aims we will use our expertise in the characterization of the lower airway microbiome (including the viral fraction) and the host immune profile. Therefore, this is an unprecedented opportunity to conduct the necessary exploratory investigations on paired lower airway and systemic samples from critically ill COVID-19 patients. Lay summary. Acute COVID-19 infection has had unprecedented effects on human health with critically ill patients suffering high critical care resources and mortality. In this project, we will use and expand our biorepository of lower airway and blood samples to explore novel ways to determine molecular signatures that can predict patients’ poor clinical outcomes.