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
- 来源:
- 关键词:AcuteAddressAirway DiseaseAntigen PresentationAntiviral ResponseB-LymphocytesBloodCD8-Positive T-LymphocytesCOVID-19COVID-19 complicationsCOVID-19 patientCXCL13 geneCell secretionCellsCellular Indexing of Transcriptomes and Epitopes by SequencingChronicChronic Lung InjuryClinicalCoculture TechniquesComplexDataDependenceDiseaseDisease ProgressionDyspneaElementsEpitopesEquilibriumEvolutionFibrosisFlow CytometryGene ExpressionGenetic TranscriptionHomingImmuneImmune systemIn VitroInflammationInflammation MediatorsInflammatoryInterferon Type IIKnowledgeLungLung diseasesMachine LearningMapsMeasuresMediatorMethodsMolecularMonitorNatureOligonucleotidesOutcomePathogenicityPathway interactionsPatientsPhenotypePlasmaPopulationPositioning AttributeProcessProteinsPulmonary FibrosisPulmonary InflammationPulmonary PathologyRecoveryResolutionRhinovirus infectionRiskSARS-CoV-2 antigenSamplingSeveritiesSortingSpecificitySpecimenStainsStatistical MethodsT-LymphocyteT-bet proteinTestingTissuesVirusWorkairway inflammationcell typechemokinecohortcombinatorialcoronavirus diseasecytokinedesigndisease phenotypeexhaustexhaustionexperiencehuman modelin vitro testingin vivoinnovationlung imaginglung injurymachine learning methodmigrationmolecular dynamicsmolecular targeted therapiesnew therapeutic targetnovelpotential biomarkerprogramsprotein complexresponsesenescencesevere COVID-19single-cell RNA sequencingsynergismtooltranscription factortranscriptome
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Research Grant