Th17 extracellular trap-mediated antimicrobial host defense in acne vulgaris
寻常痤疮中 Th17 细胞外陷阱介导的抗菌宿主防御
基本信息
- 批准号:10502200
- 负责人:
- 金额:$ 43.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-06 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcneAcne VulgarisAffectAffinityAntigen-Presenting CellsBacteriaBindingBiologicalBiopsyCarbohydratesCell Differentiation processCellsChromatinChronicClone CellsComplexCoupledCutaneousDNADataDefense MechanismsDendritic CellsDevelopmentDiseaseEducationEquilibriumExposure toFutureGene Expression ProfileGenesGenus staphylococcusGoalsHelper-Inducer T-LymphocyteHistone H2BHomeostasisHost DefenseHumanImageImmuneImmune responseImmune systemImmunologic TechniquesInflammasomeInflammationInflammatoryInflammatory ResponseInterferonsInterleukin-10Interleukin-17JournalsLeadLesionLigandsLightLipoproteinsMass Spectrum AnalysisMediatingMedicalMetagenomicsMethodologyModelingMolecularNonlyticNucleotidesPathway interactionsPatientsPersonsPlayProbioticsProteomicsPsychological ImpactPsychological StressPublic HealthResearchResolutionRoleScanning Electron MicroscopySignal TransductionSkinSpecificityT-LymphocyteTLR1 geneTLR2 geneTLR6 geneTestingTimeantimicrobialantimicrobial peptidebasecell typeclinical investigationdesigndisabilitydysbiosisexperimental studyextracellulargenetic elementgenetic signatureimprovedinnovationinsightkeratinocytelipidomicsmicrobialmicrobiomemicrobiome sequencingmonocyteneutrophilnovelnovel strategiesnovel therapeutic interventionpathogenpathogenic bacteriapotential biomarkerreceptorresponseself esteemsingle-cell RNA sequencingskin disorderskin lesionskin microbiometargeted treatmenttherapeutic targettranscriptomicswhole genome
项目摘要
PROJECT SUMMARY
Acne vulgaris, or acne, is a disease of the pilosebaceous unit (PSU). Acne is ranked third among
chronic skin diseases for causing disability and medical expense and is a major cause of psychological stress
in young people. One factor contributing to acne is Cutibacterium acnes, the major bacterial species in the
PSU. Using C. acnes as a model to study the interaction between the microbiome and the host immune
response, we: 1) previously demonstrated the presence of IL-17 in acne skin lesions and 2) recently
discovered that C. acnes phylotypes associated with acne (CA) or healthy skin (CH) differentially regulate the
fate of TH17 cells to develop into non-antimicrobial (n-AMTH17) and antimicrobial (AMTH17) subsets. AMTH17 cells
release T cell extracellular traps (TETs) and directly kill C. acnes and other bacteria pathogens.
To date, the mechanisms by which C. acnes phylotypes induce TETs and their biological impact in
acne are unknown. Therefore, our proposed research is innovative because we will define the immune
landscape of the acne lesions, provide mechanistic insights into the biological impact of TH17-TET formation in
acne, and identify novel immune pathways and potential biomarkers that can be targeted for acne therapy.
This is important as future strategies could be developed to modulate TH17 function. Additionally, maintaining
the balance among the different phylotypes of C. acnes may represent a strategy for novel probiotic design.
The identification of C. acnes ligands will further elucidate the specificity of host receptors involved in microbial
surveillance and lead to the development of novel therapeutic approaches
skin diseases caused by dysbiosis.
to control acne and other human
Our central hypothesis is that innate activation of TH17 cells leads to induction of antimicrobial
mechanisms, including TETs, which contribute to host defense against C. acnes and other bacteria. To
elucidate this, we will determine the antimicrobial mechanisms of AMTH17 cells against C. acnes (Aim 1),
investigate the role of AMTH17 cells in acne inflammation (Aim 2), and identify the C. acnes ligands that induce
AMTH17 differentiation (Aim 3). Our preliminary findings support the premise that healthy skin commensals are
critical to the education of our immune system and our overall defense against pathogens. Our strategy will
include: classical immunological techniques involving T cell cloning to dissect the immune effector functions
that underlie TH17-mediated antimicrobial host defense; microbiome sequencing of C. acnes phylotypes that
inhabit donor biopsies to define how interactions within the skin microbiome and the host immune response
influences acne development; high-resolution time-lapse imaging to define mechanisms of TET release and
chromatin dynamics that occur during TET formation; scanning electron microscopy to delimit extracellular trap
formation in human T cells; and state-of-the-art single cell RNA-seq experiments to compute T cell gene
signatures and to define the T cell types and immune circuits present in acne lesions. Additional state-of-the-
art methodologies include the use of high affinity capture of cellular interactomes, coupled with mass
spectrometry-based proteomics, lipidomics and carbohydrate HPAEC-PAD analysis to identify C. acnes
ligands and endogenous complexes. This contribution is significant as, our studies will make significant
conceptual advances in our understanding of T cell–antimicrobial defense mechanisms, and allow major
advances in the understanding of the immune networks in acne that can be targeted for therapy
项目摘要
寻常痤疮或痤疮是一种毛囊皮脂腺单位(PSU)疾病。痤疮是排名第三,
慢性皮肤病造成残疾和医疗费用,是心理压力的主要原因
在年轻人中。导致痤疮的一个因素是痤疮皮肤杆菌,其是痤疮皮肤中的主要细菌物种。
电源。利用C.痤疮作为研究微生物组与宿主免疫之间相互作用的模型
响应,我们:1)以前证明了痤疮皮肤病变中存在IL-17,2)最近
发现C.与痤疮(CA)或健康皮肤(CH)相关的痤疮类型差异性地调节
TH 17细胞发育成非抗微生物(n-AMTH 17)和抗微生物(AMTH 17)亚群的命运。AMTH 17细胞
释放T细胞胞外陷阱(Tcells extracellular traps,Tcells)直接杀伤C.痤疮和其他细菌病原体。
迄今为止,C.痤疮痤疮类型诱导THBE及其生物学影响
痤疮是未知的。因此,我们提出的研究是创新的,因为我们将定义免疫
痤疮病变的景观,提供了对TH 17-泰特形成的生物学影响的机制见解,
痤疮,并确定新的免疫途径和潜在的生物标志物,可以针对痤疮治疗。
这是重要的,因为未来的策略可以开发来调节TH 17功能。此外,维护
C.痤疮可能代表了一种新的益生菌设计策略。
对C.痤疮配体将进一步阐明参与微生物感染的宿主受体的特异性,
监测,并导致新的治疗方法的发展
由生态失调引起的皮肤病。
控制痤疮和其他人类疾病
我们的中心假设是TH 17细胞的先天激活导致抗微生物剂的诱导。
机制,其中包括Tactinase,这有助于宿主防御C。痤疮和其他细菌。到
阐明这一点,我们将确定AMTH 17细胞对C.痤疮(目标1),
研究AMTH 17细胞在痤疮炎症中的作用(目的2),并鉴定C.痤疮配体诱导
AMTH 17分化(Aim 3)。我们的初步研究结果支持这样一个前提,即健康的皮肤是
这对我们的免疫系统教育和我们对病原体的整体防御至关重要。我们的战略将
包括:涉及T细胞克隆的经典免疫学技术,以剖析免疫效应子功能
TH 17介导的抗微生物宿主防御的基础; C.痤疮类型,
栖息供体活检,以确定皮肤微生物组和宿主免疫反应之间的相互作用
影响痤疮的发展;高分辨率延时成像,以确定泰特释放的机制,
泰特形成期间发生的染色质动力学;扫描电子显微镜以界定细胞外陷阱
以及最先进的单细胞RNA-seq实验来计算T细胞基因的表达。
特征,并确定T细胞类型和免疫电路存在于痤疮病变。额外的国家-
现有技术的方法包括使用细胞相互作用体的高亲和力捕获,
基于光谱的蛋白质组学、脂质组学和碳水化合物HPAEC-PAD分析来鉴定C.痤疮
配体和内源性复合物。这一贡献是重要的,因为我们的研究将使重要的
我们对T细胞抗菌防御机制的理解的概念性进展,并允许主要的
对痤疮免疫网络的了解进展,可用于治疗
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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George W Agak其他文献
Keloids: Does patients’ sex influence the presentation and recurrence post-excision?
- DOI:
10.1016/j.bjps.2021.08.030 - 发表时间:
2022-01-01 - 期刊:
- 影响因子:
- 作者:
Nangole F. Wanjala;Githaiga Joseph;Mamati Anthony;O. Primus;James J. Ogeng'o;Omu Anzala;Isabella Dohil;George W Agak - 通讯作者:
George W Agak
George W Agak的其他文献
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{{ truncateString('George W Agak', 18)}}的其他基金
Th17 extracellular trap-mediated antimicrobial host defense in acne vulgaris
寻常痤疮中 Th17 细胞外陷阱介导的抗菌宿主防御
- 批准号:
10698121 - 财政年份:2022
- 资助金额:
$ 43.7万 - 项目类别:
The nature of Propionibacterium acnes-induced inflammatory immune responses in acne vulgaris
痤疮丙酸杆菌诱导寻常痤疮炎症免疫反应的性质
- 批准号:
10596361 - 财政年份:2017
- 资助金额:
$ 43.7万 - 项目类别:
The nature of Propionibacterium acnes-induced inflammatory immune responses in acne vulgaris
痤疮丙酸杆菌诱导寻常痤疮炎症免疫反应的性质
- 批准号:
9898322 - 财政年份:2017
- 资助金额:
$ 43.7万 - 项目类别:
The nature of Propionibacterium acnes-induced inflammatory immune responses in acne vulgaris
痤疮丙酸杆菌诱导寻常痤疮炎症免疫反应的性质
- 批准号:
9293615 - 财政年份:2017
- 资助金额:
$ 43.7万 - 项目类别:
The nature of Propionibacterium acnes-induced inflammatory immune responses in acne vulgaris
痤疮丙酸杆菌诱导寻常痤疮炎症免疫反应的性质
- 批准号:
10153687 - 财政年份:2017
- 资助金额:
$ 43.7万 - 项目类别:
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