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 是导致 COVID-19 大流行的原因，从中国武汉出现并迅速传播 世界各地。这次大流行的一个特点是 SARS-CoV-2 进化枝的反复出现和 令人关注的变种，其中一些已被证明具有增强的传播性。其他方面 然而，这些谱系仍不清楚。 375 万人死亡中的绝大多数是由 SARS-CoV-2 造成的 是严重肺炎的结果。在这些患者中，肺部持续的 SARS-CoV-2 病毒复制导致 缓慢进展的肺损伤和随后的呼吸衰竭。然而我们对遗传的理解 由于肺泡腔采样困难，SARS-CoV-2 在肺部的进化受到限制 并将病毒样本与可靠且全面的临床数据联系起来。在这方面，成功的临床 肺炎治疗反应 (SCRIPT) 系统生物学中心提供理想的基础设施来收集 来自新冠肺炎患者的深肺病毒样本以及相应的免疫反应和临床元数据 19. 我们建议利用 SCRIPT 的临床和研究基础设施来研究 SARS-CoV-2 变体 和宿主内适应。我们将扩展 SCRIPT，将患者表型与病毒基因型联系起来。我们的 假设 SARS-CoV-2 进化枝影响 COVID-19 肺炎的严重程度，并且病毒 患有严重肺炎的患者肺部出现多样性。为了检验我们的假设，我们将 执行以下具体目标： 目标 1. 我们将确定特定的 SARS-CoV-2 进化枝是否是 与更大的疾病严重程度或改变的宿主反应有关。我们将对 SARS-CoV-2 进行测序 从我们机构的 COVID-19 患者总库生物库以及以下患者的 BAL 样本中分离出来 对患有严重 COVID-19 肺炎的患者进行插管以确定其基因型。之间的关联 将寻求两个人群中特定的 SARS-CoV-2 进化枝以及疾病严重程度和结果。目标 2. 我们 将检查宿主肺部 SARS-CoV-2 病毒序列随时间变化的演变 重症 COVID-19 肺炎患者。对于长期呼吸衰竭的一部分患者，我们将 使用纵向收集的连续 BAL 对病毒分离株进行测序并检查宿主免疫反应 样品。这些数据将用于量化肺部的病毒动力学，以绘制宿主内病毒的出现情况 病毒准种，以表征这些变化引起的宿主免疫反应，并将 这些特点与患者的临床情况有关。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 感染严重程度的特征。病毒进化枝数据将与以下措施相结合 宿主免疫反应（BAL 流体流式细胞术和细胞因子水平）和患者临床元数据 开发一个综合模型来预测哪些患者将患上特别严重的 COVID-19 疾病。