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

基本信息

批准号：
10510084
负责人：
Leopoldo Nicolas Segal
金额：
$ 25.25万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10510084
关键词：
2019-nCoV Acute Antibody Response Area Aspirate substance Biological Response Modifiers Blood Blood Circulation Blood specimen Bronchoalveolar Lavage Bronchoscopy COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 severity Caring Cells Clinical Communities 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 Lead Light 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 United States Viral Virus Replication bacteriome biobank clinical heterogeneity experience host-microbe interactions metabolome metabolomics microbial microbial host mortality mortality risk multiple omics novel novel marker pathogen respiratory microbiome response sample collection septic patients single-cell RNA sequencing trait transcriptome transcriptomics virome

项目摘要

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.

摘要：纽约地区在美国 COVID-19 大流行初期就面临病例激增的情况。国家导致多个医疗保健系统不稳定，无法满足医疗保健的高需求重症监护的使用和死亡率。重症 COVID-19 患者的异质性演变，高死亡率。延长 ICU 住院时间凸显了需要更好地了解个体的内型，这可能会暴露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。我们有这些危重 SARS-CoV-2 感染患者的下呼吸道样本和血液样本。已经探索了下呼吸道微生物环境，包括病毒组、细菌组和宿主免疫在我们最近的报告中，我们使用了 142 名重症 COVID-19 患者的下呼吸道横截面样本。在《自然微生物学》上发表的患者中，我们发现了与不良相关的微生物和宿主特征结果，主要是由于病毒复制控制不良、抗 Spike/抗 RBD IgG 反应减弱所致然而，为了了解这种不良病毒的机制。控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。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，在此应用中，我们将使用现有的生物存储库并用新的方法对其进行扩展。案例来检验以下假设：利用新型 scRNA 测序进行气道和全身内分型代谢组学方法预测重症 SARS-CoV-2 患者的预后较差，因此，我们建议。扩大和优化我们危重 SARS-CoV-2 患者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，从而对气道进行内型分析和系统环境来评估与不良临床结果的关联（R33 阶段）。为了实现这些目标，我们将利用我们在下呼吸道微生物组（包括病毒因此，这是进行必要的研究的前所未有的机会。对重症 COVID-19 患者的配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 感染对危重患者的健康产生了前所未有的影响。在这个项目中，我们将使用和扩大我们的重症监护资源和死亡率。下呼吸道和血液样本的生物样本库，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。