Immune Programs and Related T Cell Mechanisms of Pulmonary Complications After COVID-19 Illness

COVID-19 疾病后肺部并发症的免疫程序和相关 T 细胞机制

基本信息

  • 批准号:
    10886167
  • 负责人:
  • 金额:
    $ 41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

SUMMARY Patients who survive severe COVID-19 illness are at risk of developing pulmonary complications. While this may resolve, some patients experience progression of their disease, resulting in severe lung damage. Although T cells are critical to anti-viral responses in the lungs, sustained T-cell alterations in the blood after COVID-19 illness implicates them in persistent disease. There is a major knowledge gap regarding if, and how, circulating T cells contribute to lung pathology. Our understanding is hampered by the variable clinical nature of pulmonary disease, as well as the challenges to identifying pathogenic T cells in the blood and defining relationships to disease course. The current project overcomes these barriers by applying innovative single-cell methods and powerful machine learning tools that are exquisitely tailored to detect disease-relevant cell populations in the blood, and to define the cellular and molecular dynamics that constitute immune programs governing pulmonary complications of COVID-19. The study leverages a unique and highly characterized cohort of COVID-19 patients defined by their severity of acute illness and developing fibrosis. By garnering data on hundreds of cellular and molecular features in a large sample of patients, we are now poised to significantly advance the field. Preliminary findings reveal pulmonary phenotypes that discriminate severe airway disease, and perturbations in discrete CD4+ and CD8+ T-cell populations, including IFN-γ-producing virus-specific cells, related to these clinical entities. A shared feature of T cells identified is their expression of T-bet, a transcription factor also expressed by tissue-homing B cells that persist after COVID-19 illness. Further, our data support an interplay between these T cells and B cells. Accordingly, we will test the overarching hypothesis that sustained perturbations in novel CD4+ and CD8+ T cells expressing T-bet, including virus-specific cells, mark pro-fibrotic pulmonary phenotypes. These cells create a persistent feedforward circuit of IFN-γ-dependent inflammation through coordinated actions with B cells. First, immune programs of pulmonary disease will be defined and their trajectories mapped in relation to progression and recovery on the basis of concerted T cells, other immune cells and inflammatory mediators operating in vivo over 2 years. This will involve resolving protein signatures and gene expression profiles of T cells at unprecedented depth to determine their functions and evolution (Aim 1). Next, the contributions of epitope-specific T cells to divergent recovery paths will be distinguished in order to address how progression and resolution is regulated by virus epitopes (Aim 2). To this end, a combinatorial tetramer method will monitor the proportions and functions of up to 6 epitope specificities within each subject. Finally, we will confirm the ability for pathogenic T cells from subjects with developing fibrosis, to synergize with T-bet+ B cells by promoting IFN-γ-dependent inflammation in vitro, through a process involving a novel potential biomarker of disease progression, CXCL13 (Aim 3). Assembling “elements of the T-cell puzzle” will identify mechanisms of disease that reveal new therapeutic targets for halting or reversing lung inflammation after COVID-19 illness.
总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Judith A Woodfolk其他文献

Use of a novel air cleaner to monitor airborne allergen
  • DOI:
    10.1016/s0091-6749(02)81248-9
  • 发表时间:
    2002-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Natalie J Custis;Judith A Woodfolk;John W Vaughan;Thomas AE Platts-Mills
  • 通讯作者:
    Thomas AE Platts-Mills

Judith A Woodfolk的其他文献

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{{ truncateString('Judith A Woodfolk', 18)}}的其他基金

Protective and Pathogenic T Cells Responding to SARS-CoV-2 in Health and Disease
健康和疾病中对 SARS-CoV-2 做出反应的保护性和致病性 T 细胞
  • 批准号:
    10218954
  • 财政年份:
    2021
  • 资助金额:
    $ 41万
  • 项目类别:
Protective and Pathogenic T Cells Responding to SARS-CoV-2 in Health and Disease
健康和疾病中对 SARS-CoV-2 做出反应的保护性和致病性 T 细胞
  • 批准号:
    10488185
  • 财政年份:
    2021
  • 资助金额:
    $ 41万
  • 项目类别:
Regulation of TSLP receptor expression and function in eczema in mice and man
小鼠和人湿疹中 TSLP 受体表达和功能的调节
  • 批准号:
    8651423
  • 财政年份:
    2011
  • 资助金额:
    $ 41万
  • 项目类别:
Regulation of TSLP receptor expression and function in eczema in mice and man
小鼠和人湿疹中 TSLP 受体表达和功能的调节
  • 批准号:
    8106840
  • 财政年份:
    2011
  • 资助金额:
    $ 41万
  • 项目类别:
Regulation of TSLP receptor expression and function in eczema in mice and man
小鼠和人湿疹中 TSLP 受体表达和功能的调节
  • 批准号:
    8460063
  • 财政年份:
    2011
  • 资助金额:
    $ 41万
  • 项目类别:
Regulation of TSLP receptor expression and function in eczema in mice and man
小鼠和人湿疹中 TSLP 受体表达和功能的调节
  • 批准号:
    8244445
  • 财政年份:
    2011
  • 资助金额:
    $ 41万
  • 项目类别:
ATOPIC DERMATITIS: SKIN AND IMMUNE RESPONSE TO REDUCED ALLERGEN EXPOSURE
特应性皮炎:皮肤和免疫对减少过敏原暴露的反应
  • 批准号:
    8167150
  • 财政年份:
    2010
  • 资助金额:
    $ 41万
  • 项目类别:
ATOPIC DERMATITIS: SKIN AND IMMUNE RESPONSE TO REDUCED ALLERGEN EXPOSURE
特应性皮炎:皮肤和免疫对减少过敏原暴露的反应
  • 批准号:
    7951462
  • 财政年份:
    2009
  • 资助金额:
    $ 41万
  • 项目类别:
ATOPIC DERMATITIS: SKIN AND IMMUNE RESPONSE TO REDUCED ALLERGEN EXPOSURE
特应性皮炎:皮肤和免疫对减少过敏原暴露的反应
  • 批准号:
    7718542
  • 财政年份:
    2008
  • 资助金额:
    $ 41万
  • 项目类别:
ATOPIC DERMATITIS: SKIN AND IMMUNE RESPONSE TO REDUCED ALLERGEN EXPOSURE
特应性皮炎:皮肤和免疫对减少过敏原暴露的反应
  • 批准号:
    7606686
  • 财政年份:
    2007
  • 资助金额:
    $ 41万
  • 项目类别:

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