Impact of COPD on Lung-Resident MAIT Cell Frequency, Function and Recognition of Bacterial Infection
COPD 对肺驻留 MAIT 细胞频率、功能和细菌感染识别的影响
基本信息
- 批准号:10291804
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAerosolsAntigensBacteriaBacterial InfectionsBiological AssayCD8-Positive T-LymphocytesCause of DeathCell Death InductionCell SurvivalCell physiologyCellsCellular biologyChronic Obstructive Airway DiseaseContainmentCost of IllnessCustomDataDevelopmentDiagnosisDiseaseDisease ProgressionDustEpithelial CellsFlow CytometryFluorescence MicroscopyFrequenciesFunctional disorderGene ExpressionGeneral PopulationGrowthHost DefenseHumanImmuneImpairmentIndividualInfectionInfiltrationInflammationInflammatoryInterferon Type IILinkLower Respiratory Tract InfectionLungLung diseasesMHC InteractionMediatingMolecular BiologyMucous MembraneNontypable Haemophilus influenzaOutcomePathogenesisPathologyPathway interactionsPatientsPopulationPrevalencePseudomonas aeruginosaRNARisk FactorsRoleSeverity of illnessSilicon DioxideSmokeSmokerSmokingStreptococcus pneumoniaeStructure of parenchyma of lungT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTherapeuticTimeUnited StatesVeteransVirus DiseasesWorkairway epitheliumairway inflammationairway obstructionairway remodelingantimicrobialcell killingcellular pathologycigarette smokecostcytokinecytotoxiccytotoxic CD8 T cellsdirect applicationimprovedmacrophagemilitary veteranneutrophilpalliativepathogenpathogenic bacteriaperipheral bloodpulmonary functionrecruitrespiratoryrespiratory pathogenresponsestandard caretreatment strategy
项目摘要
Chronic Obstructive Pulmonary Disease (COPD) is now the 3rd leading cause of death in the United States,
and the only cause of death that is on the rise. Smoking is the most common risk factor for COPD, however
there are other environmental triggers such as dust, smoke, sand, or aerosols. Nearly one in ten VA patients
are diagnosed with COPD and the costs associated with these patients are ten times higher than for all other
conditions. Despite the prevalence of COPD, our understanding of the immune mechanisms that drive
development of the disease is incomplete. There is increasing evidence that cytotoxic CD8+ T cells are critical
to the pathology of COPD. Work done by the PI and collaborators has identified mucosal associated invariant
T (MAIT) cells as an ‘innate’-like lung-resident CD8+ T cell population capable of recognizing airway epithelial
cells infected with COPD-associated lung pathogens. Although lower airway bacterial infections are associated
with COPD and are correlated with airway function, the mechanisms by which infections develop and
contribute to COPD pathogenesis is not yet clear. Because CD8+ T cells recognize and destroy target cells
infected with pathogens, lung-resident CD8+ T cells like MAIT cells may be important for containment of
bacterial infections. In fact, we find that MAIT cells, which are highly enriched in human airways, have reduced
frequency in the peripheral blood of COPD patients. Furthermore, we find that MAIT cells, while capable of
controlling the growth of bacteria, are impaired in their ability to make IFN-g in response to bacterially infected
airway epithelial cells from patients with COPD. The effect of COPD on MAIT cell function is not known and
may be essential to understanding how lower respiratory infections contribute to the development of COPD
and COPD exacerbations.
This proposal is focused on determining the mechanisms by which COPD alters the frequency and function of
MAIT cells, particularly with regard to recognition of bacterially infected airway epithelial cells. Additionally, we
will determine the consequences of altered MAIT cell activation on bacterial survival and inflammation.
This project contains two Aims:
Aim 1. Define the frequency and functional capacity of MAIT cells among CD8+ T cells from COPD
lungs.
Aim 2. Define the mechanisms underlying MAIT cell-mediated killing of bacteria, and how these
mechanisms are modulated in COPD.
慢性阻塞性肺疾病(COPD)现在是美国第三大死亡原因,
也是唯一一个正在上升的死亡原因。然而,吸烟是COPD最常见的危险因素,
还有其他的环境诱因,如灰尘、烟雾、沙子或气溶胶。近十分之一的VA患者
被诊断患有COPD,与这些患者相关的费用是所有其他患者的十倍。
尽管COPD的患病率,我们对免疫机制的理解,
越来越多的证据表明,细胞毒性CD 8 + T细胞是至关重要的
PI和合作者所做的工作已经确定了粘膜相关的不变
T(MAIT)细胞作为一种能够识别气道上皮细胞的“先天性”类CD 8 + T细胞群
尽管下呼吸道细菌感染与慢性阻塞性肺病相关的肺病原体有关,
与COPD相关,并与气道功能、感染发展的机制以及
由于CD 8 + T细胞识别并破坏靶细胞,
感染病原体后,肺部驻留的CD 8 + T细胞如MAIT细胞可能对遏制
事实上,我们发现MAIT细胞,在人类气道中高度富集,
此外,我们发现MAIT细胞虽然能够在COPD患者的外周血中表达,
控制细菌生长的细胞,在细菌感染时产生IFN-γ的能力受损,
COPD对MAIT细胞功能的影响尚不清楚,
对于了解下呼吸道感染如何促进COPD的发展可能至关重要
和COPD恶化。
该建议的重点是确定COPD改变肺动脉高压发生频率和功能的机制。
MAIT细胞,特别是在识别细菌感染的气道上皮细胞方面。
将决定改变MAIT细胞活化对细菌存活和炎症的影响。
该项目有两个目标:
目的1.确定COPD患者CD 8 + T细胞中MAIT细胞的频率和功能
肺
目的2.明确MAIT细胞介导的细菌杀伤的机制,以及这些机制是如何发挥作用的。
在COPD中调节机制。
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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Melanie J Harriff其他文献
Melanie J Harriff的其他文献
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{{ truncateString('Melanie J Harriff', 18)}}的其他基金
Impact of COPD on Lung-Resident MAIT Cell Frequency, Function and Recognition of Bacterial Infection
COPD 对肺驻留 MAIT 细胞频率、功能和细菌感染识别的影响
- 批准号:
9892960 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Distinct pathways for MR1 antigen presentation upon infection with intracellular versus extracellular pathogens
细胞内和细胞外病原体感染时 MR1 抗原呈递的不同途径
- 批准号:
9883714 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Mtb uptake and antigen presentation in human lung epithelial cells
人肺上皮细胞中结核分枝杆菌的摄取和抗原呈递
- 批准号:
8391103 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Mtb uptake and antigen presentation in human lung epithelial cells
人肺上皮细胞中结核分枝杆菌的摄取和抗原呈递
- 批准号:
8244008 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Mtb uptake and antigen presentation in human lung epithelial cells
人肺上皮细胞中结核分枝杆菌的摄取和抗原呈递
- 批准号:
8595290 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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