Assessing SARS-CoV-2 Variant Evolution in Patients

评估患者中的 SARS-CoV-2 变异进化

基本信息

  • 批准号:
    10426993
  • 负责人:
  • 金额:
    $ 74.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
新冠肺炎大流行的起因SARS-CoV-2从武汉出现,中国,并迅速传播 环游世界。这次大流行的一个特点是反复出现SARS-CoV-2分支和 令人担忧的变种,其中一些已被证明具有更强的传播性。的其他方面 然而,这些血统仍然不清楚。SARS-CoV-2造成的375万人死亡中的绝大多数 都是严重肺炎的结果。在这些患者中,正在进行的SARS-CoV-2病毒在肺部复制导致 到缓慢发展的肺损伤和随后的呼吸衰竭。然而,我们对基因的理解 SARS-CoV-2在肺部的进化有限,因为难以采集肺泡腔样本 并将病毒样本与强大而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COVID患者的深肺病毒样本和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变种 和宿主内适应。我们将扩展脚本,将患者表型与病毒基因型联系起来。我们的 假设SARS-CoV-2亚型影响新冠肺炎肺炎的严重程度 经历严重肺炎的患者的肺部会进化出多样性。为了检验我们的假设,我们将 实现以下具体目标:目标1.我们将确定特定的SARS-CoV-2分支是否 与更严重的疾病或改变的宿主反应有关。我们将对SARS-CoV-2病毒进行测序 分离自本机构新冠肺炎患者的生物库和BAL样本 对新冠肺炎重症肺炎插管患者进行基因分型。两者之间的关联 将寻求两个人群中特定的SARS-CoV-2分支和疾病严重程度和结果。目标2.我们 将研究宿主内SARS-CoV-2病毒序列随时间在肺内的演变变化 重症新冠肺炎肺炎患者。在长期呼吸衰竭的患者中,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测宿主免疫反应 样本。这些数据将被用来量化肺部的病毒动态,绘制宿主内部出现的 病毒准种,以表征由这些变化引起的宿主免疫反应,并相互关联 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分支基因组信息与临床和宿主免疫反应相结合 预测新冠肺炎感染严重程度的功能。病毒分支数据将与以下措施相结合 宿主免疫反应(BAL液流式细胞仪和细胞因子水平)和患者临床元数据 开发一个全面的模型,预测哪些患者会患上特别严重的新冠肺炎病。

项目成果

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ALAN R HAUSER其他文献

ALAN R HAUSER的其他文献

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{{ truncateString('ALAN R HAUSER', 18)}}的其他基金

Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10641659
  • 财政年份:
    2022
  • 资助金额:
    $ 74.99万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10827545
  • 财政年份:
    2022
  • 资助金额:
    $ 74.99万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10333874
  • 财政年份:
    2022
  • 资助金额:
    $ 74.99万
  • 项目类别:
Medical Scientist Training Program
医学科学家培训计划
  • 批准号:
    10664364
  • 财政年份:
    2022
  • 资助金额:
    $ 74.99万
  • 项目类别:
High-Risk Clones of Pseudomonas aeruginosa
铜绿假单胞菌的高风险克隆
  • 批准号:
    10294368
  • 财政年份:
    2021
  • 资助金额:
    $ 74.99万
  • 项目类别:
High-Risk Clones of Pseudomonas aeruginosa
铜绿假单胞菌的高风险克隆
  • 批准号:
    10408175
  • 财政年份:
    2021
  • 资助金额:
    $ 74.99万
  • 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
  • 批准号:
    10222524
  • 财政年份:
    2020
  • 资助金额:
    $ 74.99万
  • 项目类别:
Dynamics of Pseudomonas aeruginosa During Bacteremia
菌血症期间铜绿假单胞菌的动态
  • 批准号:
    10042352
  • 财政年份:
    2020
  • 资助金额:
    $ 74.99万
  • 项目类别:
Systems Biology Modeling of Severe Hospital-Acquired Pneumonia
严重医院获得性肺炎的系统生物学模型
  • 批准号:
    10551467
  • 财政年份:
    2018
  • 资助金额:
    $ 74.99万
  • 项目类别:
Pathogen and Microbiome Temporal Changes During Resolution of HAP
HAP 消退过程中病原体和微生物组的时间变化
  • 批准号:
    10097985
  • 财政年份:
    2018
  • 资助金额:
    $ 74.99万
  • 项目类别:

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