Assessing SARS-CoV-2 Variant Evolution in Patients

评估患者中的 SARS-CoV-2 变异进化

• 批准号: 10426993
• 负责人: ALAN R HAUSER
• 金额: $ 74.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-29 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426993
• 关键词: 2019-nCoV; Acinetobacter baumannii; Alveolar; Archives; Bacterial Pneumonia; Breathing; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 pneumonia; COVID-19 severity; Cause of Death; China; Clinical; Clinical Data; Computer Models; Data; Development; Disease; Disease Outcome; Disease Progression; Evolution; Flow Cytometry; Funding; Genome; Genotype; Goals; Immune; Immune response; Infection; Inflammation; Infrastructure; Injury; Institution; Integration Host Factors; Klebsiella; Knowledge; Link; Lung; Maps; Measurement; Measures; Mechanical ventilation; Metadata; Morbidity - disease rate; Mutate; Mutation; National Institute of Allergy and Infectious Disease; Outcome; Patients; Phenotype; Pneumonia; Population; Process; Pseudomonas aeruginosa; RNA; Research Infrastructure; Respiratory Failure; Risk; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Severity of illness; Staphylococcus aureus; Systems Biology; Testing; Time; Viral; Virus; Virus Replication; Work; Writing; bacteriome; biobank; clinical infrastructure; cohort; cytokine; experience; genetic evolution; insight; microbiome; mortality; pandemic disease; pathogen; patient subsets; pneumonia treatment; predictive modeling; response; severe COVID-19; single-cell RNA sequencing; variants of concern; virus envelope

SARS-CoV-2, the cause of the COVID-19 pandemic, emerged from Wuhan, China, and rapidly spread around the world. A feature of the pandemic has been the repeated emergence of SARS-CoV-2 clades and variants of concern, some of which have been shown to have enhanced transmissibility. Other aspects of these lineages, however, remain unclear. The vast majority of the 3.75 million deaths caused by SARS-CoV-2 are the result of severe pneumonia. In these patients, ongoing SARS-CoV-2 viral replication in the lungs leads to slowly progressing pulmonary injury and subsequent respiratory failure. Yet our understanding of the genetic evolution of SARS-CoV-2 in the lungs is limited because of difficulties sampling the pulmonary alveolar space and in linking viral samples to robust and comprehensive clinical data. In this regard, the Successful Clinical Response in Pneumonia Therapy (SCRIPT) Systems Biology Center provides the ideal infrastructure to collect deep-lung viral samples and corresponding immune response and clinical metadata from patients with COVID- 19. We propose to leverage the clinical and research infrastructure of SCRIPT to study SARS-CoV-2 variants and intra-host adaptation. We will expand SCRIPT to link patient phenotypes with virus genotypes. Our hypothesis is that SARS-CoV-2 clades influence the severity of COVID-19 pneumonia and that viral diversity evolves in the lungs of patients experiencing severe pneumonia. To test our hypotheses, we will perform the following specific aims: Aim 1. We will determine whether specific SARS-CoV-2 clades are associated with greater disease severity or altered host response. We will sequence SARS-CoV-2 isolates from a biobank of a general pool of COVID-19 patients at our institution and from BAL samples of intubated patients with severe COVID-19 pneumonia to establish their genotypes. Associations between specific SARS-CoV-2 clades and disease severity and outcomes in both populations will be sought. Aim 2. We will examine the evolution of intra-host SARS-CoV-2 viral sequence changes over time in the lungs of patients with severe COVID-19 pneumonia. In a subset of patients with prolonged respiratory failure, we will sequence viral isolates and examine the host immune response using longitudinally collected serial BAL samples. These data will be used to quantify viral dynamics in the lung, to map the intra-host emergence of viral quasi-species, to characterize the host immune responses elicited by these changes, and to correlate these features with the clinical conditions of the patients. Aim 3. We will generate a computational model that integrates SARS-CoV-2 clade genome information with clinical and host immune response features to predict the severity of COVID-19 infections. Viral clade data will be integrated with measures of the host immune response (BAL fluid flow cytometry and cytokine levels) and patient clinical metadata to develop a comprehensive model that predicts which patients will develop especially severe COVID-19 disease.

SARS-COV-2是COVID-19大流行的原因，来自中国武汉，并迅速传播 世界各地。大流行的一个特征是SARS-COV-2进化枝的反复出现和 令人关注的变体，其中一些已被证明具有增强的传播性。其他方面 但是，这些血统仍不清楚。由SARS-COV-2造成的375万人死亡中的绝大多数 是严重肺炎的结果。在这些患者中，肺导线中正在进行的SARS-COV-2病毒复制 慢慢发展肺部损伤和随后的呼吸衰竭。但是我们对遗传的理解 由于很难取样肺肺泡空间，因此肺中SARS-COV-2的演变受到限制 并将病毒样品与稳健且全面的临床数据联系起来。在这方面，成功的临床 肺炎治疗（脚本）系统生物学中心的反应提供了理想的基础设施 深肺病毒样品以及来自共vid-患者的相应免疫反应和临床元数据 19。我们建议利用脚本的临床和研究基础设施来研究SARS-COV-2变体 和主宿内适应。我们将扩展脚本以将患者表型与病毒基因型联系起来。我们的 假设是SARS-COV-2进化枝会影响Covid-19-19肺炎的严重程度和病毒 患有严重肺炎的患者的肺部多样性演变。为了检验我们的假设，我们将 执行以下特定目的：目标1。我们将确定特定的SARS-COV-2进化枝是否为 与更大的疾病严重程度或宿主反应改变有关。我们将序列SARS-COV-2序列 来自我们机构中共vid-19患者的一般生物库的生物库，并从BAL样品中 患有严重covid-199肺炎的插管患者以确定其基因型。之间的关联 将寻求特定的SARS-COV-2进化枝，疾病的严重程度和结果。目标2。我们 将检查主宿内SARS-COV-2病毒序列随时间变化的演变 患有严重covid-19-19肺炎的患者。在长时间呼吸衰竭患者的一部分中，我们将 序列病毒分离株并使用纵向收集的串行BAL检查宿主免疫反应 样品。这些数据将用于量化肺中的病毒动力学，以绘制 病毒准物种，以表征这些变化引起的宿主免疫反应，并相关 这些特征具有患者的临床状况。目标3。我们将生成一个计算模型 将SARS-COV-2进化枝基因组信息与临床和宿主免疫反应相结合 预测Covid-19感染的严重程度的特征。病毒进化枝数据将与 宿主免疫反应（BAL流体流式细胞仪和细胞因子水平）和患者临床元数据 开发一个综合模型，该模型可以预测哪些患者将患上特别严重的Covid-19疾病。