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

生物样本库优化和用于重症 SARS-COV-2 感染患者内型分析

• 批准号: 10684890
• 负责人: Leopoldo Nicolas Segal
• 金额: $ 20.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684890
• 关键词: 2019-nCoV; Acute; Antibody Response; Area; Biological Response Modifiers; Blood; Blood specimen; Bronchoalveolar Lavage; Bronchoscopy; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; Caring; Cells; Circulation; Clinical; Communities; Credentialing; Critical Care; Critical Illness; Disease; Ensure; Environment; Etiology; Event; Evolution; Funding; Future; Grant; Health; Healthcare Systems; Human; Immune; Immune response; Immunoglobulin G; Individual; Infrastructure; Investigation; Mediating; Microbiology; Molecular; Molecular Profiling; Nature; New York; New York City; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase; Physicians; Population; Process; Protocols documentation; Publications; Publishing; Reporting; Research; Resources; SARS-CoV-2 infection; Sampling; Sampling Studies; Secure; Source; Standardization; Testing; Time; Trachea; United States; Viral; Viremia; Virus Replication; aspirate; bacteriome; biobank; clinical heterogeneity; experience; host-microbe interactions; metabolome; metabolomics; microbial; mortality; mortality risk; multiple omics; novel; novel marker; pathogen; prognostication; respiratory microbiome; response; sample collection; septic patients; single-cell RNA sequencing; trait; transcriptome; transcriptomics; virome

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.

抽象。在美国COVID-19大流行的早期，纽约市地区面临着病例激增的问题。 导致多种卫生保健系统不稳定的国家，无法满足对 重症监护使用和死亡率。重症COVID-19患者的异质性演变，高死亡率 长期的ICU停留强调了更好地了解个体的内型的必要性， 这些脓毒症患者的可治疗特征。当第一批病例到达纽约大学时，我们建立了一个生物储存库， 下呼吸道的样本和这些重症SARS-CoV-2感染患者的血液。我们有 已经探索了下呼吸道微生物环境，包括病毒组、细菌组和宿主免疫 反应在我们最近的报告中，使用了142例重症COVID-19患者的横截面下呼吸道样本， 发表在《自然微生物学》上的患者，我们确定了与不良反应相关的微生物和宿主特征。 结局，主要由病毒复制控制不佳、抗刺突/抗RBD IgG应答减弱驱动 和独特的宿主转录组学特征。然而，为了了解这种可怜的病毒的机制， 我们需要在更早的时间点和纵向研究样本。我们目前正在使用这些样本 以表征纵向病毒和宿主转录组动态。然而，关键的分子免疫 介质需要使用代谢组学方法进行探索，而不同的细胞免疫反应可能 需要单细胞方法。在此应用中，我们将使用现有的生物储存库，并使用新的 案例来检验使用新型scRNA测序进行气道和全身内定型的假设， 代谢组学方法预测重症SARS-CoV-2患者预后不良。因此，我们建议 扩大和优化我们在重症SARS-CoV-2患者中的气道和全身样本的生物储存库（R21 阶段），以便进行scRNA测序和代谢组学方法，以便对气道进行内定型 和全身环境，以评价与不良临床结局的相关性（R33期）。完成 这些目标，我们将利用我们的专业知识，在下呼吸道微生物组（包括病毒）的表征， 级分）和宿主免疫谱。因此，这是一个前所未有的机会，进行必要的 对重症COVID-19患者的成对下呼吸道和全身样本进行探索性研究。 简单总结。急性COVID-19感染对人类健康产生了前所未有的影响， 重症监护资源和死亡率高的患者。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储存库，以探索确定分子特征的新方法， 可以预测患者的不良临床结果。