Neutrophil Heterogeneity and Immunopathogenesis of COVID-19 ARDS
COVID-19 ARDS 的中性粒细胞异质性和免疫发病机制
基本信息
- 批准号:10560925
- 负责人:
- 金额:$ 57.41万
- 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:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAcuteAcute Lung InjuryAcute Respiratory Distress SyndromeAgeAntibodiesBilateralBloodBlood Coagulation DisordersBlood PlateletsBronchoalveolar Lavage FluidCOVID-19COVID-19 patientCOVID-19 vaccineCOVID-19/ARDSCellsChemotaxisCirculationClinicalCollaborationsCytometryCytoplasmic GranulesDataDevelopmentDiseaseDisease ProgressionEconomicsExocytosisFCGR3B geneFibrin fragment DFunctional disorderGene ExpressionHemorrhageHeterogeneityHospitalizationHost DefenseImmuneIn VitroIndividualInflammation MediatorsInflammatoryInflammatory ResponseIntensive Care UnitsInterleukin-6LifeLungLymphocyteMeasuresMyeloid-derived suppressor cellsNeutrophil InfiltrationOutcomePatient TransferPatientsPatternPersonal SatisfactionPhagocytosisPlasmaPlatelet ActivationPneumoniaPopulationProteomeProteomicsPsyche structurePulmonary InflammationReactive Oxygen SpeciesReportingRespiratory BurstRoleSeverity of illnessSurfaceSystemT-LymphocyteTNF geneTherapeutic InterventionVariantViralantimicrobialchemokinecytokinecytokine release syndromedensityeffective therapyextracellularimmune activationimmunothrombosisin vivoinhibitorinsightlung injurymouse modelmultiple omicsneutrophilnovelnovel markernovel therapeutic interventionpandemic diseasepathogenic viruspharmacologicpost SARS-CoV-2 infectionprospectiveresponsesevere COVID-19sexsystemic inflammatory responsetherapeutic targettherapeutically effectivetissue injurytranscriptome sequencingtranscriptomic profilingtranscriptomics
项目摘要
Project Summary
Coronavirus disease 2019 (COVID-19) is a potentially life-threatening disease caused by the novel viral
pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the 10%-20% of COVID-19
patients hospitalized, approximately 1/3 develop acute respiratory distress syndrome (ARDS). COVID-19-
induced ARDS results from a combination of virally induced lung injury and the rapid influx of immune cells that
release inflammatory mediators leading to a hyper-activated state known as cytokine storm. Understanding the
pathophysiology of COVID-19 ARDS is critical to finding effective therapeutic interventions. Accumulating
evidence indicates critical roles for neutrophils in both ARDS and immunothrombosis in COVID-19. Multi-omics
studies identified dramatic neutrophil heterogeneity in COVID-19, including emergence of a large number of
low density neutrophils (LDN). We reported a novel population of LDN present in both the circulation and lungs
of severe COVID-19 patients which expresses intermediate levels of CD16 (CD16Int LDN). CD16Int LDN
spontaneously form neutrophil extracellular traps (NETs), activate platelets in vivo and in vitro, and have
heightened degranulation. Our preliminary data show that LDN subsets from severe COVID-19 patients are
functionally distinct from mature, normal density neutrophils (NDN). Based on these findings, we postulate
that differential functional responses of heterogeneous neutrophil populations collaborate to induce
systemic and pulmonary inflammation leading to ARDS in COVID-19 patients. Three specific Aims are
proposed to further dissect the underlying mechanisms. Aim 1 will comprehensively characterize neutrophil
subsets from severe/critical COVID-19 patients using proteomics and transcriptomics approaches. The
information gained from those studies will be used to refine our CyTOF antibody panel and prospectively
measure dynamic changes of neutrophil subsets over the disease course in COVID-19 patients. Aim 2 will
determine neutrophil subset functional changes during disease progression and their contributions to
dysregulated inflammatory response and coagulopathy in severe/critical COVID-19 patients. Neutrophil
degranulation, NET formation, phagocytosis, chemotaxis, T cell suppressive activity, and cytokine/chemokine
release will be examined. We will also determine if LDN subsets and NDN or their derived products promote
coagulopathy in COVID-19 patients. Aim 3 will determine the relative contributions of neutrophil host defense
systems to development of acute lung injury. We will also use a hACE2 Tg mouse model to determine the
roles of neutrophil respiratory burst, granule exocytosis, and NET formation to SARS-CoV-2-induced acute
lung inflammation. Successful completion of this proposal will provide novel insights into COVID-19-induced
ARDS pathophysiology by defining the functional roles of different neutrophil subsets and by establishing
which host defense systems of neutrophils as a therapeutic target for inhibiting inflammatory lung injury and
immunothrombosis in COVID-19.
项目摘要
2019年冠状病毒病(COVID-19)是一种由新型病毒引起的可能危及生命的疾病,
病原体,严重急性呼吸综合征冠状病毒2(SARS-CoV-2)。在COVID-19的10%-20%中,
住院患者中,约1/3发展为急性呼吸窘迫综合征(ARDS)。COVID-19-
诱导的ARDS是由病毒诱导的肺损伤和免疫细胞的快速流入的组合引起的,
释放炎症介质,导致称为细胞因子风暴的过度活化状态。了解
COVID-19 ARDS的病理生理学对于寻找有效的治疗干预至关重要。积累
有证据表明,中性粒细胞在COVID-19的ARDS和免疫血栓形成中发挥着关键作用。多组学
研究发现,COVID-19中的中性粒细胞具有显著的异质性,包括大量中性粒细胞的出现。
低密度中性粒细胞(LDN)。我们报道了一种新的LDN人群,存在于循环和肺中。
表达中等水平CD 16(CD 16 Int LDN)的严重COVID-19患者。CD16Int LDN
自发形成中性粒细胞胞外陷阱(NET),在体内和体外激活血小板,
严重的脱颗粒我们的初步数据显示,来自严重COVID-19患者的LDN亚群
在功能上不同于成熟的正常密度中性粒细胞(NDN)。基于这些发现,我们假设
异质性中性粒细胞群体的不同功能反应协同诱导
导致COVID-19患者ARDS的全身和肺部炎症。三个具体目标是
建议进一步剖析潜在的机制。目的1将全面表征中性粒细胞
使用蛋白质组学和转录组学方法从严重/危重COVID-19患者的亚群中提取。的
从这些研究中获得的信息将用于改进我们的CyTOF抗体组,
测量COVID-19患者病程中中性粒细胞亚群的动态变化。目标2将
确定疾病进展过程中中性粒细胞亚群功能的变化及其对
重症/危重COVID-19患者的炎症反应失调和凝血功能障碍。中性粒
脱粒、NET形成、吞噬作用、趋化性、T细胞抑制活性和细胞因子/趋化因子
释放将被审查。我们还将确定LDN子集和NDN或其衍生产品是否促进
COVID-19患者的凝血功能障碍。目的3将确定中性粒细胞宿主防御的相对贡献
急性肺损伤的发生发展。我们还将使用hACE 2 Tg小鼠模型来确定
中性粒细胞呼吸爆发、颗粒胞吐和NET形成在SARS-CoV-2诱导急性肺损伤中的作用
肺部炎症成功完成该提案将为COVID-19引起的
通过确定不同中性粒细胞亚群的功能作用,
其宿主中性粒细胞的防御系统作为抑制炎性肺损伤的治疗靶点,
COVID-19免疫血栓形成。
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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Jiapeng Huang其他文献
Jiapeng Huang的其他文献
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{{ truncateString('Jiapeng Huang', 18)}}的其他基金
Low Density Neutrophils Link Inflammation and Coagulopathy in COVID-19
低密度中性粒细胞与 COVID-19 中的炎症和凝血病有关
- 批准号:
10276657 - 财政年份:2022
- 资助金额:
$ 57.41万 - 项目类别:
Low Density Neutrophils Link Inflammation and Coagulopathy in COVID-19
低密度中性粒细胞与 COVID-19 中的炎症和凝血病有关
- 批准号:
10708740 - 财政年份:2022
- 资助金额:
$ 57.41万 - 项目类别:
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