The cellular mechanisms of immunological memory development in COVID-19 patients

COVID-19患者免疫记忆发展的细胞机制

基本信息

  • 批准号:
    10745497
  • 负责人:
  • 金额:
    $ 32.14万
  • 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:
    2021-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

The recent unexpected emergence of the COVID-19 pandemic has spurred significant interest in an improved understanding of immunological memory to SARS-CoV-2, which consists of humoral (neutralizing antibodies) and cellular (T and B cells) memory. The generation of immunological memory to the SARS-CoV-2 virus critically depends on T cell responses. During a viral infection, CD4 helper T cells differentiate largely into either Th1 cells that orchestrate a type I antiviral immune response or follicular helper (Tfh) cells that enhance antibody production. CD8 T cells clonally expand and acquire effector function to directly kill virus-infected cells. Despite the heterogeneity and clonal diversity of virus-specific T cells, the majority of effector T cells die after viral clearance and only a small portion of them develop into memory T cells that provide long-lasting protection for the host. Similarly, B cells develop into memory B cells and long-lived plasma cells that produce neutralizing antibodies. Snapshot observations with multi-parameter flow cytometry-based assays along the course of infection has yielded abundant knowledge of T cell phenotypic and functional diversity. However, approaches as such fail to address the developmental trajectory of virus-specific T cells. This becomes more obvious in human studies given that lineage tracing by genetic alterations or adoptive transfer experiments, done easily in mice, are inherently difficult or impossible in humans. In this proposal, we will first combine newly developed single- cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) techniques on the same cells and use TCR sequences as natural barcodes to directly “lineage trace” each patient’s SARS-CoV-2-specific CD4 and CD8 T cell effector response and memory formation at the single-cell level throughout the course of natural infection. Furthermore, we will perform gene regulatory network (GRN) analysis to delineate which transcription factors collaboratively regulate virus-specific CD4 and CD8 T cell differentiation trajectories. Next, we will measure T cell clonal diversity and the quality of T cell memory from COVID-19 patients as well as healthy human controls. The latter will be used to gauge the possible presence of pre-existing immunity (PEI) in the form of memory T cells derived from cross-reactivity to common coronaviruses. These measurements will use high- throughput RNA-seq of TCR amplicons and scRNA-seq of memory T cells from recall cultures as inputs for computational TCR motif analysis. Lastly, successful vaccine development relies on an advanced understanding of the types of Tfh cells that are generated during natural infection and how they interact with B cells as well as T regulatory cells for anti-SARS-CoV-2 antibody production in humans. To this end, we propose to monitor circulating Tfh cells, including three major populations (Th1-, Th2- and Th17-like subsets), and T follicular regulatory (Tfr) cells in both SARS-Cov-2-infected and healthy human control subjects. In addition, we will perform T cell-B cell coculture assays to dissect the functional contributions of each subset of Tfh cells and how they interact with Tfr cells in regulating anti-SARS-CoV-2 neutralizing antibody responses.
最近COVID-19大流行的意外出现激发了人们对改善健康状况的极大兴趣

项目成果

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WEIGUO CUI其他文献

WEIGUO CUI的其他文献

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{{ truncateString('WEIGUO CUI', 18)}}的其他基金

Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10743327
  • 财政年份:
    2022
  • 资助金额:
    $ 32.14万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10209655
  • 财政年份:
    2021
  • 资助金额:
    $ 32.14万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10591599
  • 财政年份:
    2021
  • 资助金额:
    $ 32.14万
  • 项目类别:
Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages
Pim1 激酶协调 PPAR gamma 通路和线粒体功能,介导巨噬细胞中的促动脉粥样硬化反应
  • 批准号:
    10372226
  • 财政年份:
    2021
  • 资助金额:
    $ 32.14万
  • 项目类别:
The cellular mechanisms of immunological memory development in COVID-19 patients
COVID-19患者免疫记忆发展的细胞机制
  • 批准号:
    10465343
  • 财政年份:
    2021
  • 资助金额:
    $ 32.14万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10721409
  • 财政年份:
    2019
  • 资助金额:
    $ 32.14万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10536743
  • 财政年份:
    2019
  • 资助金额:
    $ 32.14万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10428867
  • 财政年份:
    2019
  • 资助金额:
    $ 32.14万
  • 项目类别:
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
T 细胞耗竭中的表型、功能和转录异质性
  • 批准号:
    10311054
  • 财政年份:
    2019
  • 资助金额:
    $ 32.14万
  • 项目类别:
The Cellular and Transcriptional Control of CD8 T Cell Functional Adaptation to Chronic Viruses
CD8 T 细胞功能适应慢性病毒的细胞和转录控制
  • 批准号:
    9160163
  • 财政年份:
    2016
  • 资助金额:
    $ 32.14万
  • 项目类别:

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The cellular mechanisms of immunological memory development in COVID-19 patients
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    10465343
  • 财政年份:
    2021
  • 资助金额:
    $ 32.14万
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    10630125
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  • 资助金额:
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